“Find Me” and “Eat Me” signals: tools to drive phagocytic processes for modulating antitumor immunity

Abstract

Phagocytosis, a vital defense mechanism, involves the recognition and elimination of foreign substances by cells. Phagocytes, such as neutrophils and macrophages, rapidly respond to invaders; macrophages are especially important in later stages of the immune response. They detect “find me” signals to locate apoptotic cells and migrate toward them. Apoptotic cells then send “eat me” signals that are recognized by phagocytes via specific receptors. “Find me” and “eat me” signals can be strategically harnessed to modulate antitumor immunity in support of cancer therapy. These signals, such as calreticulin and phosphatidylserine, mediate potent pro-phagocytic effects, thereby promoting the engulfment of dying cells or their remnants by macrophages, neutrophils, and dendritic cells and inducing tumor cell death. This review summarizes the phagocytic “find me” and “eat me” signals, including their concepts, signaling mechanisms, involved ligands, and functions. Furthermore, we delineate the relationships between “find me” and “eat me” signaling molecules and tumors, especially the roles of these molecules in tumor initiation, progression, diagnosis, and patient prognosis. The interplay of these signals with tumor biology is elucidated, and specific approaches to modulate “find me” and “eat me” signals and enhance antitumor immunity are explored. Additionally, novel therapeutic strategies that combine “find me” and “eat me” signals to better bridge innate and adaptive immunity in the treatment of cancer patients are discussed.

Keywords

cancer immunotherapy / CARL / CX3CL1 / “Eat me” signal / “Find me” signal / Fc / LPC / Phagocytosis / PtSer, SLAMF7

References

[1] Dale DC, Boxer L, Liles WC. The phagocytes: neutrophils and monocytes. Blood. 2008; 112(4): 935–945.

[2] Guilliams M, Ginhoux F, Jakubzick C, Naik SH, Onai N, Schraml BU, et al. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat Rev Immunol. 2014; 14(8): 571–578.

[3] Ugel S, Canè S, De Sanctis F, Bronte V. Monocytes in the tumor microenvironment. Annu Rev Pathol. 2021; 16: 93–122.

[4] Ravichandran KS. Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums. J Exp Med. 2010; 207(9): 1807–1817.

[5] Mehrotra P, Ravichandran KS. Drugging the efferocytosis process: concepts and opportunities. Nat Rev Drug Discov. 2022; 21(8): 601–620.

[6] Galloway DA, Phillips AEM, Owen DRJ, Moore CS. Phagocytosis in the Brain: Homeostasis and Disease. Front Immunol. 2019; 10: 790.

[7] Chen L, Han X. Anti–PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest. 2015; 125(9): 3384–3391.

[8] Wang J, Lu Q, Chen X, Aifantis I. Targeting MHC-I inhibitory pathways for cancer immunotherapy. Trends Immunol. 2024; 45(3): 177–187.

[9] Wu X, Li T, Jiang R, Yang X, Guo H, Yang R. Targeting MHC-I molecules for cancer: function, mechanism, and therapeutic prospects. Mol Cancer. 2023; 22(1): 194.

[10] Chen H, Chen Y, Deng M, John S, Gui X, Kansagra A, et al. Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells. J Immunother Cancer. 2020; 8(2): e000515.

[11] Zhang P, Zheng P, Liu Y. Amplification of the CD24 gene is an independent predictor for poor prognosis of breast cancer. Front Genet. 2019; 10: 461459.

[12] Shapira S, Kazanov D, Mdah F, Yaakobi H, Herishanu Y, Perry C, et al. Feasibly of CD24/CD11b as a screening test for hematological malignancies. J Pers Med. 2021; 11(8): 724.

[13] Medina-Echeverz J, Eggert T, Han M, Greten TF. Hepatic myeloid-derived suppressor cells in cancer. Cancer Immunol Immunother. 2015; 64(8): 931–940.

[14] Stossel TP. On the crawling of animal cells. Science. 1993; 260(5111): 1086–1094.

[15] Kim MK, Huang ZY, Hwang PH, Jones BA, Sato N, Hunter S, et al. Fcgamma receptor transmembrane domains: role in cell surface expression, gamma chain interaction, and phagocytosis. Blood. 2003; 101(11): 4479–4484.

[16] Lauber K, Bohn E, Kröber SM, Xiao Y-j, Blumenthal SG, Lindemann RK, et al. Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell. 2003; 113(6): 717–730.

[17] Ogretmen B. Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer. 2018; 18(1): 33–50.

[18] Horino K, Nishiura H, Ohsako T, Shibuya Y, Hiraoka T, Kitamura N, et al. A monocyte chemotactic factor, S19 ribosomal protein dimer, in phagocytic clearance of apoptotic cells. Lab Invest. 1998; 78(5): 603–617.

[19] Murakami Y, Tian L, Voss OH, Margulies DH, Krzewski K, Coligan JE. CD300b regulates the phagocytosis of apoptotic cells via phosphatidylserine recognition. Cell Death Differ. 2014; 21(11): 1746–1757.

[20] Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S. Identification of a factor that links apoptotic cells to phagocytes. Nature. 2002; 417(6885): 182–187.

[21] Jaiswal S, Jamieson CH, Pang WW, Park CY, Chao MP, Majeti R, et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell. 2009; 138(2): 271–285.

[22] Oldenborg P-A, Gresham HD, Lindberg FP. CD47-signal regulatory protein alpha (SIRPalpha) regulates Fcgamma and complement receptor-mediated phagocytosis. J Exp Med. 2001; 193(7): 855–862.

[23] Gordon SR, Maute RL, Dulken BW, Hutter G, George BM, McCracken MN, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature. 2017; 545(7655): 495–499.

[24] Chen X, Lu Q, Zhou H, Liu J, Nadorp B, Lasry A, et al. A membrane-associated MHC-I inhibitory axis for cancer immune evasion. Cell. 2023; 186(18): 3903–3920. e21.

[25] Moesta AK, Li XY, Smyth MJ. Targeting CD39 in cancer. Nat Rev Immunol. 2020; 20(12): 739–755.

[26] Lu X. Structure and Function of Ligand CX3CL1 and its Receptor CX3CR1 in Cancer. Curr Med Chem. 2022; 29(41): 6228–6246.

[27] Nishiura H, Kawakami T, Kawabe M, Kato-Kogoe N. Yamada N, Nakasho K, et al. RP S19 C-terminal peptide trimer acts as a C5a receptor antagonist. Biochem Biophys Rep. 2016; 7: 70–76.

[28] Hochreiter-Hufford AE, Lee CS, Kinchen JM, Sokolowski JD, Arandjelovic S, Call JA, et al. Phosphatidylserine receptor BAI1 and apoptotic cells as new promoters of myoblast fusion. Nature. 2013; 497(7448): 263–267.

[29] DeKruyff RH, Bu X, Ballesteros A, Santiago C, Chim YL, Lee HH, et al. T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J Immunol. 2010; 184(4): 1918–1930.

[30] Ichimura T, Asseldonk EJ, Humphreys BD, Gunaratnam L, Duffield JS, Bonventre JV. Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells. J Clin Invest. 2008; 118(5): 1657–1668.

[31] Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity. 2016; 44(5): 989–1004.

[32] Savill J, Gregory C. Apoptotic PS to Phagocyte TIM-4: Eat Me. Immunity. 2007; 27(6): 830–832.

[33] Park SY, Jung MY, Kim HJ, Lee SJ, Kim SY, Lee BH, et al. Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor. Cell Death Differ. 2008; 15(1): 192–201.

[34] Park S-Y, Yun Y, Lim J-S, Kim M-J. Kim S-Y, Kim J-E. et al. Stabilin-2 modulates the efficiency of myoblast fusion during myogenic differentiation and muscle regeneration. Nat Commun. 2016; 7(1): 10871.

[35] Kinchen JM, Cabello J, Klingele D, Wong K, Feichtinger R, Schnabel H, et al. Two pathways converge at CED-10 to mediate actin rearrangement and corpse removal in C. elegans. Nature. 2005; 434(7029): 93–99.

[36] Simhadri VR, Andersen JF, Calvo E, Choi S-C, Coligan JE, Borrego F. Human CD300a binds to phosphatidylethanolamine and phosphatidylserine, and modulates the phagocytosis of dead cells. Blood. 2012; 119(12): 2799–2809.

[37] Borrego F. The CD300 molecules: an emerging family of regulators of the immune system. Blood. 2013; 121(11): 1951–1960.

[38] Akakura S, Singh S, Spataro M, Akakura R, Kim JI, Albert ML, et al. The opsonin MFG-E8 is a ligand for the alphavbeta5 integrin and triggers DOCK180-dependent Rac1 activation for the phagocytosis of apoptotic cells. Exp Cell Res. 2004; 292(2): 403–416.

[39] Asano K, Miwa M, Miwa K, Hanayama R, Nagase H, Nagata S, et al. Masking of phosphatidylserine inhibits apoptotic cell engulfment and induces autoantibody production in mice. J Exp Med. 2004; 200(4): 459–467.

[40] Nakano T, Ishimoto Y, Kishino J, Umeda M, Inoue K, Nagata K, et al. Cell adhesion to phosphatidylserine mediated by a product of growth arrest-specific gene 6. J Biol Chem. 1997; 272(47): 29411–29414.

[41] Anderson HA, Maylock CA, Williams JA, Paweletz CP, Shu H, Shacter E. Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Nat Immunol. 2003; 4(1): 87–91.

[42] Graham DK, DeRyckere D, Davies KD, Earp HS. The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer. 2014; 14(12): 769–785.

[43] Myers KV, Amend SR, Pienta KJ. Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment. Mol Cancer. 2019; 18(1): 94.

[44] Savill J, Hogg N, Ren Y, Haslett C. Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J Clin Invest. 1992; 90(4): 1513–1522.

[45] Munerati M, Cortesi R, Ferrari D, Di Virgilio F, Nastruzzi C. Macrophages loaded with doxorubicin by ATP-mediated permeabilization: Potential carriers for antitumor therapy. Biochim Biophys Acta. 1994; 1224(2): 269–276.

[46] de Andrade Mello P, Bian S, Savio LEB, Zhang H, Zhang J, Junger W, et al. Hyperthermia and associated changes in membrane fluidity potentiate P2×7 activation to promote tumor cell death. Oncotarget. 2017; 8(40): 67254–67268.

[47] Qi B, Yu T, Wang C, Wang T, Yao J, Zhang X, et al. Shock wave-induced ATP release from osteosarcoma U2OS cells promotes cellular uptake and cytotoxicity of methotrexate. J Exp Clin Cancer Res. 2016; 35(1): 161.

[48] Kashyap AS, Thelemann T, Klar R, Kallert SM, Festag J, Buchi M, et al. Antisense oligonucleotide targeting CD39 improves anti-tumor T cell immunity. J Immunother Cancer. 2019; 7(1): 67.

[49] Wang YX, Martin-McNulty B. da Cunha V, Vincelette J, Lu X, Feng Q, et al. Fasudil, a Rho-kinas. inhibitor, attenuates angiotensin II-induced abdominal aortic aneurysm in apolipoprotein E-deficient mice by inhibiting apoptosis and proteolysis. Circulation. 2005; 111(17): 2219–2226.

[50] Takamura M, Sakamoto M, Genda T, Ichida T, Asakura H, Hirohashi S. Inhibition of intrahepatic metastasis of human hepatocellular carcinoma by Rho-associated protein kinase inhibitor Y-27632. Hepatology. 2001; 33(3): 577–581.

[51] Chen J, Xie J, Jiang Z, Wang B, Wang Y, Hu X. Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. Oncogene. 2011; 30(42): 4297–4306.

[52] Medina CB, Mehrotra P, Arandjelovic S, Perry JSA, Guo Y, Morioka S, et al. Metabolites released from apoptotic cells act as tissue messengers. Nature. 2020; 580(7801): 130–135.

[53] Brown GC. Cell death by phagocytosis. Nat Rev Immunol. 2024; 24(2): 91–102.

[54] Lauber K, Bohn E, Kröber SM, Xiao YJ, Blumenthal SG, Lindemann RK, et al. Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell. 2003; 113(6): 717–730.

[55] Kabarowski JHS, Zhu K, Le LQ, Witte ON, Xu Y. Lysophosphatidylcholine as a Ligand for the Immunoregulatory Receptor G2A. Science. 2001; 293(5530): 702–705.

[56] Hait NC, Oskeritzian CA, Paugh SW, Milstien S, Spiegel S. Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochim Biophys Acta. 2006; 1758(12): 2016–2026.

[57] Chekeni FB, Elliott MR, Sandilos JK, Walk SF, Kinchen JM, Lazarowski ER, et al. Pannexin 1 channels mediate ‘find-me’ signal release and membrane permeability during apoptosis. Nature. 2010; 467(7317): 863–867.

[58] Truman LA, Ford CA, Pasikowska M, Pound JD, Wilkinson SJ, Dumitriu IE, et al. CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood. 2008; 112(13): 5026–5036.

[59] Chen Y, Corriden R, Inoue Y, Yip L, Hashiguchi N, Zinkernagel A, et al. ATP Release Guides Neutrophil Chemotaxis via P2Y2 and A3 Receptors. Science. 2006; 314(5806): 1792–1795.

[60] Truman LA, Ford CA, Pasikowska M, Pound JD, Wilkinson SJ, Dumitriu IE, et al. CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood. 2008; 112(13): 5026–5036.

[61] Horino K, Nishiura H, Ohsako T, Shibuya Y, Hiraoka T, Kitamura N, et al. A monocyte chemotactic factor, S19 ribosomal protein dimer, in phagocytic clearance of apoptotic cells. Lab Invest. 1998; 78(5): 603–617.

[62] Wakasugi K, Schimmel P. Highly differentiated motifs responsible for two cytokine activities of a split human tRNA synthetase. J Biol Chem. 1999; 274(33): 23155–23159.

[63] Wakasugi K, Schimmel P. Two distinct cytokines released from a human aminoacyl-tRNA synthetase. Science. 1999; 284(5411): 147–151.

[64] Behrensdorf HA, van de Craen M, Knies UE, Vandenabeele P, Clauss M. The endothelial monocyte-activating polypeptide II (EMAP II) is a substrate for caspase-7. FEBS Lett. 2000; 466(1): 143–147.

[65] Hou Y, Plett PA, Ingram DA, Rajashekhar G, Orschell CM, Yoder MC, et al. Endothelial-monocyte–activating polypeptide II induces migration of endothelial progenitor cells via the chemokine receptor CXCR3. Exp Hematol. 2006; 34(8): 1125–1132.

[66] Peter C, Waibel M, Radu CG, Yang LV, Witte ON, Schulze-Osthoff K. et al. Migration to apoptotic “find-me” signals is mediated via the phagocyte receptor G2A. J Biol Chem. 2008; 283(9): 5296–5305.

[67] McMurray HF, Parthasarathy S, Steinberg D. Oxidatively modified low density lipoprotein is a chemoattractant for human T lymphocytes. J Clin Invest. 1993; 92(2): 1004–1008.

[68] Kim SJ, Gershov D, Ma X, Brot N, Elkon KB. I-PLA(2) activation during apoptosis promotes the exposure of membrane lysophosphatidylcholine leading to binding by natural immunoglobulin M antibodies and complement activation. J Exp Med. 2002; 196(5): 655–665.

[69] Atsumi G-i, Murakami M, Tajima M, Shimbara S, Hara N, Kudo I. The perturbed membrane of cells undergoing apoptosis is susceptible to type II secretory phospholipase A2 to liberate arachidonic acid. Biochim Biophys Acta. 1997; 1349(1): 43–54.

[70] Kim SJ, Gershov D, Ma X, Brot N, Elkon KB. I-PLA2 Activation during Apoptosis Promotes the Exposure of Membrane Lysophosphatidylcholine Leading to Binding by Natural Immunoglobulin M Antibodies and Complement Activation. J Exp Med. 2002; 196(5): 655–665.

[71] Lauber K, Blumenthal SG, Waibel M, Wesselborg S. Clearance of Apoptotic Cells: Getting Rid of the Corpses. Mol Cell. 2004; 14(3): 277–287.

[72] Peter C, Waibel M, Keppeler H, Lehmann R, Xu G, Halama A, et al. Release of lysophospholipid ‘find-me’ signals during apoptosis requires the ATP-binding cassette transporter A1. Autoimmunity. 2012; 45(8): 568–573.

[73] Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A, Walk SF, et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature. 2009; 461(7261): 282–286.

[74] Jacob F, Pérez Novo C, Bachert C, Van Crombruggen K. Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses. Purinergic Signal. 2013; 9(3): 285–306.

[75] Gorini S, Gatta L, Pontecorvo L, Vitiello L, la Sala A. Regulation of innate immunity by extracellular nucleotides. Am J Blood Res. 2013; 3(1): 14–28.

[76] Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic Cell Death in Cancer Therapy. Annu Rev Immunol. 2013; 31(1): 51–72.

[77] Wang Y, Martins I, Ma Y, Kepp O, Galluzzi L, Kroemer G. Autophagy-dependent ATP release from dying cells via lysosomal exocytosis. Autophagy. 2013; 9(10): 1624–1625.

[78] Dosch M, Gerber J, Jebbawi F, Beldi G. Mechanisms of ATP Release by Inflammatory Cells. Int J Mol Sci. 2018; 19(4): 1222.

[79] Schwiebert EM. ABC transporter-facilitated ATP conductive transport. Am J Physiol. 1999; 276(1): C1–C8.

[80] Hyde SC, Emsley P, Hartshorn MJ, Mimmack MM, Gileadi U, Pearce SR, et al. Structural model of ATP-binding proteing associated with cystic fibrosis, multidrug resistance and bacterial transport. Nature. 1990; 346(6282): 362–365.

[81] Reisin IL, Prat AG, Abraham EH, Amara JF, Gregory RJ, Ausiello DA, et al. The cystic fibrosis transmembrane conductance regulator is a dual ATP and chloride channel. J Biol Chem. 1994; 269(32): 20584–20591.

[82] Roman RM, Lomri N, Braunstein G, Feranchak AP, Simeoni LA, Davison AK, et al. Evidence for Multidrug Resistance-1 P-Glycoprotein-dependent Regulation of Cellular ATP Permeability. J Membr Biol. 2001; 183(3): 165–173.

[83] Syrjanen JL, Michalski K, Chou T-H, Grant T, Rao S, Simorowski N, et al. Structure and assembly of calcium homeostasis modulator proteins. Nat Struct Mol Biol. 2020; 27(2): 150–159.

[84] Gaitán-Peñas H, Gradogna A, Laparra-Cuervo L. Solsona C, Fernández-Dueñas V, Barrallo-Gimeno A. et al. Investigation of LRRC8-Mediated Volume-Regulated Anion Currents in Xenopus Oocytes. Biophys J. 2016; 111(7): 1429–1443.

[85] Vultaggio-Poma V, Sarti AC, Di Virgilio F. Extracellular ATP: A Feasible Target for Cancer Therapy. Cells. 2020; 9(11): 2496.

[86] Brandao-Burch A, Key M, Patel J, Arnett T, Orriss I. The P2×7 Receptor is an Important Regulator of Extracellular ATP Levels. Front Endocrinol (Lausanne). 2012; 3: 41.

[87] Chekeni FB, Elliott MR, Sandilos JK, Walk SF, Kinchen JM, Lazarowski ER, et al. Pannexin 1 channels mediate ‘find-me’ signal release and membrane permeability during apoptosis. Nature. 2010; 467(7317): 863–867.

[88] Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A, Walk SF, et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature. 2009; 461(7261): 282–286.

[89] Koizumi S, Shigemoto-Mogami Y. Nasu-Tada K, Shinozaki Y, Ohsawa K, Tsuda M, et al. UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature. 2007; 446(7139): 1091–1095.

[90] Marques-da-Silva C, Burnstock G, Ojcius DM, Coutinho-Silva R. Purinergic receptor agonists modulate phagocytosis and clearance of apoptotic cells in macrophages. Immunobiology. 2011; 216(1): 1–11.

[91] Yamaguchi H, Maruyama T, Urade Y, Nagata S. Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells. Elife. 2014; 3: e02172.

[92] Ren R, Pang B, Han Y, Li Y. A Glimpse of the Structural Biology of the Metabolism of Sphingosine-1-Phosphate. Contact (Thousand Oaks). 2021; 4: 2515256421995601.

[93] Vu TM, Ishizu A-N, Foo JC, Toh XR, Zhang F, Whee DM, et al. Mfsd2b is essential for the sphingosine-1-phosphate export in erythrocytes and platelets. Nature. 2017; 550(7677): 524–528.

[94] Luo B, Gan W, Liu Z, Shen Z, Wang J, Shi R, et al. Erythropoeitin Signaling in Macrophages Promotes Dying Cell Clearance and Immune Tolerance. Immunity. 2016; 44(2): 287–302.

[95] Weigert A, Cremer S, Schmidt MV, von Knethen A, Angioni C, Geisslinger G, et al. Cleavage of sphingosine kinase 2 by caspase-1 provokes its release from apoptotic cells. Blood. 2010; 115(17): 3531–3540.

[96] Rosen H, Goetzl EJ. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol. 2005; 5(7): 560–570.

[97] Strader CR, Pearce CJ, Oberlies NH. Fingolimod (FTY720): a recently approved multiple sclerosis drug based on a fungal secondary metabolite. J Nat Prod. 2011; 74(4): 900–907.

[98] Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, et al. A new class of membrane-bound chemokine with a CX3C motif. Nature. 1997; 385(6617): 640–644.

[99] Le Y, Zhou Y, Iribarren P, Wang J. Chemokines and chemokine receptors: their manifold roles in homeostasis and disease. Cell Mol Immunol. 2004; 1(2): 95–104.

[100] Garton KJ, Gough PJ, Blobel CP, Murphy G, Greaves DR, Dempsey PJ, et al. Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). J Biol Chem. 2001; 276(41): 37993–8001.

[101] Hundhausen C, Misztela D, Berkhout TA, Broadway N, Saftig P, Reiss K, et al. The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion. Blood. 2003; 102(4): 1186–1195.

[102] Haskell CA, Cleary MD, Charo IF. Molecular uncoupling of fractalkine-mediated cell adhesion and signal transduction. Rapid flow arrest of CX3CR1-expressing cells is independent of G-protein activation. J Biol Chem. 1999; 274(15): 10053–10058.

[103] Feng L, Chen S, Garcia GE, Xia Y, Siani MA, Botti P, et al. Prevention of crescentic glomerulonephritis by immunoneutralization of the fractalkine receptor CX3CR1 rapid communication. Kidney Int. 1999; 56(2): 612–620.

[104] Legler DF, Thelen M. New insights in chemokine signaling. F1000Res. 2018; 7: 95.

[105] Yan Y, Cao S, Liu X, Harrington SM, Bindeman WE, Adjei AA, et al. CX3CR1 identifies PD-1 therapy-responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy. JCI Insight. 2018; 3(8): e97828.

[106] Pallandre JR, Krzewski K, Bedel R, Ryffel B, Caignard A, Rohrlich PS, et al. Dendritic cell and natural killer cell cross-talk: a pivotal role of CX3CL1 in NK cytoskeleton organization and activation. Blood. 2008; 112(12): 4420–4424.

[107] Imai T, Hieshima K, Haskell C, Baba M, Nagira M, Nishimura M, et al. Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell. 1997; 91(4): 521–530.

[108] Chao MP, Jaiswal S, Weissman-Tsukamoto R. Alizadeh AA, Gentles AJ, Volkmer J, et al. Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci Transl Med. 2010; 2(63): 63ra94.

[109] Gardai SJ, McPhillips KA, Frasch SC, Janssen WJ, Starefeldt A, Murphy-Ullrich JE. et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell. 2005; 123(2): 321–334.

[110] Garg AD, Krysko DV, Verfaillie T, Kaczmarek A, Ferreira GB, Marysael T, et al. A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. Embo j. 2012; 31(5): 1062–1079.

[111] Basu S, Binder RJ, Ramalingam T, Srivastava PK. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity. 2001; 14(3): 303–313.

[112] Lillis AP, Greenlee MC, Mikhailenko I, Pizzo SV, Tenner AJ, Strickland DK, et al. Murine low-density lipoprotein receptor-related protein 1 (LRP) is required for phagocytosis of targets bearing LRP ligands but is not required for C1q-triggered enhancement of phagocytosis. J Immunol. 2008; 181(1): 364–373.

[113] Poon IK, Lucas CD, Rossi AG, Ravichandran KS. Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol. 2014; 14(3): 166–180.

[114] Veillette A. SLAM-family receptors: immune regulators with or without SAP-family adaptors. Cold Spring Harb Perspect Biol. 2010; 2(3): a002469.

[115] Veillette A. Immune regulation by SLAM family receptors and SAP-related adaptors. Nat Rev Immunol. 2006; 6(1): 56–66.

[116] Chen J, Zhong MC, Guo H, Davidson D, Mishel S, Lu Y, et al. SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin. Nature. 2017; 544(7651): 493–497.

[117] Wu N, Veillette A. SLAM family receptors in normal immunity and immune pathologies. Curr Opin Immunol. 2016; 38: 45–51.

[118] Unkeless JC, Scigliano E, Freedman VH. Structure and function of human and murine receptors for IgG. Annu Rev Immunol. 1988; 6: 251–281.

[119] Hulett MD, Hogarth PM. Molecular Basis of Fc Receptor Function. In: Dixon FJ, editor. Adv Immunol. Academic Press; 1994; 57: 1–127.

[120] Fridman WH. Fc receptors and immunoglobulin binding factors. Faseb j. 1991; 5(12): 2684–2690.

[121] Nimmerjahn F, Bruhns P, Horiuchi K, Ravetch JV. FcγRIV: A Novel FcR with Distinct IgG Subclass Specificity. Immunity. 2005; 23(1): 41–51.

[122] Park D, Tosello-Trampont AC. Elliott MR, Lu M, Haney LB, Ma Z, et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature. 2007; 450(7168): 430–434.

[123] Bagalkot V, Deiuliis JA, Rajagopalan S, Maiseyeu A. “Eat me” imaging and therapy. Adv Drug Deliv Rev. 2016; 99(Pt A): 2–11.

[124] Freeman GJ, Casasnovas JM, Umetsu DT, DeKruyff RH. TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol Rev. 2010; 235(1): 172–189.

[125] Park SY, Kang KB, Thapa N, Kim SY, Lee SJ, Kim IS. Requirement of adaptor protein GULP during stabilin-2-mediated cell corpse engulfment. J Biol Chem. 2008; 283(16): 10593–10600.

[126] Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S. Identification of a factor that links apoptotic cells to phagocytes. Nature. 2002; 417(6885): 182–187.

[127] He M, Kubo H, Morimoto K, Fujino N, Suzuki T, Takahasi T, et al. Receptor for advanced glycation end products binds to phosphatidylserine and assists in the clearance of apoptotic cells. EMBO Rep. 2011; 12(4): 358–364.

[128] Yang H, Chen YZ, Zhang Y, Wang X, Zhao X, Godfroy JI, 3rd, et al. A lysine-rich motif in the phosphatidylserine receptor PSR-1 mediates recognition and removal of apoptotic cells. Nat Commun. 2015; 6: 5717.

[129] Oka K, Sawamura T, Kikuta K-i, Itokawa S, Kume N, Kita T, et al. Lectin-like oxidized low-density lipoprotein receptor 1 mediates phagocytosis of aged/apoptotic cells in endothelial cells. Proc Natl Acad Sci U S A. 1998; 95(16): 9535–9540.

[130] Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T Cells and Immune Tolerance. Cell. 2008; 133(5): 775–787.

[131] Ma Y, Adjemian S, Mattarollo SR, Yamazaki T, Aymeric L, Yang H, et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity. 2013; 38(4): 729–741.

[132] Fucikova J, Spisek R, Kroemer G, Galluzzi L. Calreticulin and cancer. Cell Res. 2021; 31(1): 5–16.

[133] Michalak M, Groenendyk J, Szabo E, Gold Leslie I, Opas M. Calreticulin, a multi-proces. calcium-buffering chaperone of the endoplasmic reticulum. Biochem J. 2009; 417(3): 651–666.

[134] Ostwald TJ, MacLennan DH. Isolation of a high affinity calcium-binding protein from sarcoplasmic reticulum. J Biol Chem. 1974; 249(3): 974–979.

[135] Nakamura K, Zuppini A, Arnaudeau S, Lynch J, Ahsan I, Krause R, et al. Functional specialization of calreticulin domains. J Cell Biol. 2001; 154(5): 961–972.

[136] Michalak M, Corbett EF, Mesaeli N, Nakamura K, Opas M. Calreticulin: one protein, one gene, many functions. Biochem J. 1999; 344(Pt 2): 281–292.

[137] Feng M, Chen JY, Weissman-Tsukamoto R. Volkmer JP, Ho PY, McKenna KM, et al. Macrophages eat cancer cells using their own calreticulin as a guide: roles of TLR and Btk. Proc Natl Acad Sci U S A. 2015; 112(7): 2145–2150.

[138] Byrne JC, J NG, Stacey KB, Coffey BM, McCarthy E, Thomas W, et al. Bruton’s tyrosine kinase is required for apoptotic cell uptake via regulating the phosphorylation and localization of calreticulin. J Immunol. 2013; 190(10): 5207–5215.

[139] Song X, Zhou Z, Li H, Xue Y, Lu X, Bahar I, et al. Pharmacologic Suppression of B7-H4 Glycosylation Restores Antitumor Immunity in Immune-Cold Breast Cancers. Cancer Discov. 2020; 10(12): 1872–1893.

[140] Afshar N, Black BE, Paschal BM. Retrotranslocation of the Chaperone Calreticulin from the Endoplasmic Reticulum Lumen to the Cytosol. Mol Cell Biol. 2005; 25(20): 8844–8853.

[141] Gasser S, Raulet DH. Activation and self-tolerance of natural killer cells. Immunol Rev. 2006; 214: 130–142.

[142] Schwartzberg PL, Mueller KL, Qi H, Cannons JL. SLAM receptors and SAP influence lymphocyte interactions, development and function. Nat Rev Immunol. 2009; 9(1): 39–46.

[143] Cannons JL, Tangye SG, Schwartzberg PL. SLAM Family Receptors and SAP Adaptors in Immunity. Annu Rev Immunol. 2011; 29(1): 665–705.

[144] Latchman Y, McKay PF, Reiser H. Identification of the 2B4 molecule as a counter-receptor for CD48. J Immunol. 1998; 161(11): 5809–5812.

[145] Brown MH, Boles K, van der Merwe PA, Kumar V, Mathew PA, Barclay AN. 2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48. J Exp Med. 1998; 188(11): 2083–2090.

[146] Dong Z, Cruz-Munoz ME. Zhong M-C, Chen R, Latour S, Veillette A. Essential function for SAP family adaptors in the surveillance of hematopoietic cells by natural killer cells. Nat Immunol. 2009; 10: 973–980.

[147] Veillette A, Dong Z, Latour S. Consequence of the SLAM-SAP Signaling Pathway in Innate-like and Conventional Lymphocytes. Immunity. 2007; 27(5): 698–710.

[148] Sayos J, Wu C, Morra M, Wang N, Zhang X, Allen D, et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature. 1998; 395(6701): 462–469.

[149] Jakus Z, Fodor S, Abram CL, Lowell CA, Mócsai A. Immunoreceptor-like signaling by beta 2 and beta 3 integrins. Trends Cell Biol. 2007; 17(10): 493–501.

[150] Li D, Xiong W, Wang Y, Feng J, He Y, Du J, et al. SLAMF3 and SLAMF4 are immune checkpoints that constrain macrophage phagocytosis of hematopoietic tumors. Sci Immunol. 2022; 7(67): eabj5501.

[151] Kim JR, Horton NC, Mathew SO, Mathew PA. CS1 (SLAMF7) inhibits production of proinflammatory cytokines by activated monocytes. Inflamm Res. 2013; 62(8): 765–772.

[152] Lee JK, Mathew SO, Vaidya SV, Kumaresan PR, Mathew PA. CS1 (CRACC, CD319) induces proliferation and autocrine cytokine expression on human B lymphocytes. J Immunol. 2007; 179(7): 4672–4678.

[153] Veillette A, Guo H. CS1, a SLAM family receptor involved in immune regulation, is a therapeutic target in multiple myeloma. Crit Rev Oncol Hematol. 2013; 88(1): 168–177.

[154] Chen S, Yang M, Du J, Li D, Li Z, Cai C, et al. The Self-Specific Activation Receptor SLAM Family Is Critical for NK Cell Education. Immunity. 2016; 45(2): 292–304.

[155] Bae J, Song W, Smith R, Daley J, Tai YT, Anderson KC, et al. A novel immunogenic CS1-specific peptide inducing antigen-specific cytotoxic T lymphocytes targeting multiple myeloma. Br J Haematol. 2012; 157(6): 687–701.

[156] Cannons JL, Tangye SG, Schwartzberg PL. SLAM family receptors and SAP adaptors in immunity. Annu Rev Immunol. 2011; 29: 665–705.

[157] Tassi I, Colonna M. The cytotoxicity receptor CRACC (CS-1) recruits EAT-2 and activates the PI3K and phospholipase Cgamma signaling pathways in human NK cells. J Immunol. 2005; 175(12): 7996–8002.

[158] Cocks BG, Chang C-CJ, Carballido JM, Yssel H, de Vries JE, Aversa G. A novel receptor involved in T-cell activation. Nature. 1995; 376(6537): 260–263.

[159] Engel P, Eck MJ, Terhorst C. The SAP and SLAM families in immune responses and X-linked lymphoproliferative disease. Nat Rev Immunol. 2003; 3(10): 813–821.

[160] Morra M, Lu J, Poy F, Martin M, Sayos J, Calpe S, et al. Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells. Embo j. 2001; 20(21): 5840–5852.

[161] Dupré L, Andolfi G, Tangye SG, Clementi R, Locatelli F, Aricò M, et al. SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells. Blood. 2005; 105(11): 4383–4389.

[162] Eissmann P, Watzl C. Molecular analysis of NTB-A signaling: a role for EAT-2 in NTB-A-mediated activation of human NK cells. J Immunol. 2006; 177(5): 3170–3177.

[163] Pérez-Quintero L-A, Roncagalli R, Guo H, Latour S, Davidson D, Veillette A. EAT-2, a SAP-lik. adaptor, controls NK cell activation through phospholipase Cγ Ca++, and Erk, leading to granule polarization. J Exp Med. 2014; 211(4): 727–742.

[164] Guo H, Cruz-Munoz ME. Wu N, Robbins M, Veillette A. Immune cell inhibition by SLAMF7 is mediated by a mechanism requiring src kinases, CD45, and SHIP-1 that is defective in multiple myeloma cells. Mol Cell Biol. 2015; 35(1): 41–51.

[165] Wu Y, Wang Q, Li M, Lao J, Tang H, Ming S, et al. SLAMF7 regulates the inflammatory response in macrophages during polymicrobial sepsis. J Clin Invest. 2023; 133(6): e150224.

[166] Freeman SA, Grinstein S. Phagocytosis: receptors, signal integration, and the cytoskeleton. Immunol Rev. 2014; 262(1): 193–215.

[167] Hamerman JA, Ni M, Killebrew JR, Chu C-L, Lowell CA. The expanding roles of ITAM adapters FcRgamma and DAP12 in myeloid cells. Immunol Rev. 2009; 232(1): 42–58.

[168] Todd RF, 3rd. The continuing saga of complement receptor type 3 (CR3). J Clin Invest. 1996; 98(1): 1–2.

[169] Bruhns P. Properties of mouse and human IgG receptors and their contribution to disease models. Blood. 2012; 119(24): 5640–5649.

[170] Reth M. Antigen receptor tail clue. Nature. 1989; 338(6214): 383–384.

[171] Cambier JC. New nomenclature for the Reth motif (or ARH1/TAM/ARAM/YXXL). Immunol Today. 1995; 16(2): 110.

[172] Kurosaki T. Genetic analysis of B cell antigen receptor signaling. Annu Rev Immunol. 1999; 17: 555–592.

[173] Hogarth PM, Pietersz GA. Fc receptor-targeted therapies for the treatment of inflammation, cancer and beyond. Nat Rev Drug Discov. 2012; 11(4): 311–331.

[174] Galvez-Cancino F, Simpson AP, Costoya C, Matos I, Qian D, Peggs KS, et al. Fcγ receptors and immunomodulatory antibodies in cancer. Nat Rev Cancer. 2024; 24(1): 51–71.

[175] Pignata C, Prasad KV, Robertson MJ, Levine H, Rudd CE, Ritz J. Fc gamma RIIIA-mediated signaling involves src-family lck in human natural killer cells. J Immunol. 1993; 151(12): 6794–6800.

[176] Ghazizadeh S, Bolen JB, Fleit HB. Physical and functional association of Src-related protein tyrosine kinases with Fc gamma RII in monocytic THP-1 cells. J Biol Chem. 1994; 269(12): 8878–8884.

[177] Kawakami Y, Yao L, Miura T, Tsukada S, Witte ON, Kawakami T. Tyrosine phosphorylation and activation of Bruton tyrosine kinase upon Fc epsilon RI cross-linking. Mol Cell Biol. 1994; 14(8): 5108–5113.

[178] Junker F, Gordon J, Qureshi O. Fc gamma receptors and their role in antigen uptake, presentation, and T cell activation. Front Immunol. 2020; 11: 547589.

[179] Daëron M. Fc receptor biology. Annu Rev Immunol. 1997; 15(1): 203–234.

[180] Cady CT, Powell MS, Harbeck RJ, Giclas PC, Murphy JR, Katial RK, et al. IgG antibodies produced during subcutaneous allergen immunotherapy mediate inhibition of basophil activation via a mechanism involving both FcγRIIA and FcγRIIB. Immunol Lett. 2010; 130(1): 57–65.

[181] Hamerman JA, Jarjoura JR, Humphrey MB, Nakamura MC, Seaman WE, Lanier LL. Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. J Immunol. 2006; 177(4): 2051–2055.

[182] Ono M, Bolland S, Tempst P, Ravetch JV. Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor Fc(gamma)RIIB. Nature. 1996; 383(6597): 263–266.

[183] Malbec O, Fong DC, Turner M, Tybulewicz VL, Cambier JC, Fridman WH, et al. Fc epsilon receptor I-associated lyn-dependent phosphorylation of Fc gamma receptor IIB during negative regulation of mast cell activation. J Immunol. 1998; 160(4): 1647–1658.

[184] Bournazos S, Gupta A, Ravetch JV. The role of IgG Fc receptors in antibody-dependent enhancement. Nat Rev Immunol. 2020; 20(10): 633–643.

[185] Morris AB, Farley CR, Pinelli DF, Adams LE, Cragg MS, Boss JM, et al. Signaling through the Inhibitory Fc Receptor FcγRIIB Induces CD8(+) T Cell Apoptosis to Limit T Cell Immunity. Immunity. 2020; 52(1): 136–150.e6.

[186] Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol. 2008; 8(1): 34–47.

[187] Birge RB, Boeltz S, Kumar S, Carlson J, Wanderley J, Calianese D, et al. Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer. Cell Death Differ. 2016; 23(6): 962–978.

[188] Yoshihama Y, Namiki H, Kato T, Shimazaki N, Takaishi S, Kadoshima-Yamaoka K. et al. Potent and Selective PTDSS1 Inhibitors Induce Collateral Lethality in Cancers with PTDSS2 Deletion. Cancer Res. 2022; 82(21): 4031–4043.

[189] Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol. 1992; 148(7): 2207–2216.

[190] Fadok VA, Bratton DL, Frasch SC, Warner ML, Henson PM. The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. Cell Death Differ. 1998; 5(7): 551–562.

[191] Segawa K, Nagata S. An Apoptotic ‘Eat Me’ Signal: Phosphatidylserine Exposure. Trends Cell Biol. 2015; 25(11): 639–650.

[192] Balasubramanian K, Mirnikjoo B, Schroit AJ. Regulated externalization of phosphatidylserine at the cell surface: implications for apoptosis. J Biol Chem. 2007; 282(25): 18357–18364.

[193] Suzuki J, Denning DP, Imanishi E, Horvitz HR, Nagata S. Xk-Related Protein 8 and CED-8 Promote Phosphatidylserine Exposure in Apoptotic Cells. Science. 2013; 341(6144): 403–406.

[194] Maruoka M, Zhang P, Mori H, Imanishi E, Packwood DM, Harada H, et al. Caspase cleavage releases a nuclear protein fragment that stimulates phospholipid scrambling at the plasma membrane. Mol Cell. 2021; 81(7): 1397–1410.e9.

[195] Sakuragi T, Kosako H, Nagata S. Phosphorylation-mediated activation of mouse Xkr8 scramblase for phosphatidylserine exposure. Proc Natl Acad Sci U S A. 2019; 116(8): 2907–2912.

[196] Wang X, Li W, Zhao D, Liu B, Shi Y, Chen B, et al. Caenorhabditis elegans transthyretin-like protein TTR-52 mediates recognition of apoptotic cells by the CED-1 phagocyte receptor. Nat Cell Biol. 2010; 12(7): 655–664.

[197] Suzuki J, Umeda M, Sims PJ, Nagata S. Calcium-dependent phospholipid scrambling by TMEM16F. Nature. 2010; 468(7325): 834–838.

[198] Grimsley C, Ravichandran KS. Cues for apoptotic cell engulfment: eat-me, don’t eat-me and come-get-me signals. Trends Cell Biol. 2003; 13(12): 648–656.

[199] Ravichandran KS. Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity. 2011; 35(4): 445–455.

[200] Dayoub AS, Brekken RA. TIMs, TAMs, and PS-antibod. targeting: implications for cancer immunotherapy. Cell Commun Signal. 2020; 18(1): 29.

[201] DeRose P, Thorpe PE, Gerber DE. Development of bavituximab, a vascular targeting agent with immune-modulating properties, for lung cancer treatment. Immunotherapy. 2011; 3(8): 933–944.

[202] Hoffman RD, Kligerman M, Sundt TM, Anderson ND, Shin HS. Stereospecific chemoattraction of lymphoblastic cells by gradients of lysophosphatidylcholine. Proc Natl Acad Sci U S A. 1982; 79(10): 3285–3289.

[203] Rolin J, Al-Jaderi Z. Maghazachi AA. Oxidized lipids and lysophosphatidylcholine induce the chemotaxis and intracellular calcium influx in natural killer cells. Immunobiology. 2013; 218(6): 875–883.

[204] Chang DH, Deng H, Matthews P, Krasovsky J, Ragupathi G, Spisek R, et al. Inflammation-associated lysophospholipids as ligands for CD1d-restricted T cells in human cancer. Blood. 2008; 112(4): 1308–1316.

[205] Kim K-H, Joo J, Park B, Park S-J, Lee WJ, Han S-S, et al. Reduced levels of N’-methyl-2-pyridone-5-carboxamide and lysophosphatidylcholine 16: 0 in the serum of patients with intrahepatic cholangiocarcinoma, and the correlation with recurrence-free survival. Oncotarget. 2017; 8(68): 112598.

[206] Kim SC, Kim MK, Kim YH, Ahn SA, Kim KH, Kim K, et al. Differential levels of L homocysteic acid and lysophosphatidylcholine (16: 0) in sera of patients with ovarian cancer. Oncol Lett. 2014; 8(2): 566–574.

[207] Zhao Z, Xiao Y, Elson P, Tan H, Plummer SJ, Berk M, et al. Plasma lysophosphatidylcholine levels: potential biomarkers for colorectal cancer. J Clin Oncol. 2007; 25(19): 2696–2701.

[208] Wolrab D, Jirásko R, Cífková E, Höring M, Mei D, Chocholoušková M, et al. Lipidomic profiling of human serum enables detection of pancreatic cancer. Nat Commun. 2022; 13(1): 124.

[209] Zeleznik OA, Clish CB, Kraft P, Avila-Pacheco J. Eliassen AH, Tworoger SS. Circulating Lysophosphatidylcholines, Phosphatidylcholines, Ceramides, and Sphingomyelins and Ovarian Cancer Risk: A 23-Year Prospective Study. J Natl Cancer Inst. 2020; 112(6): 628–636.

[210] Kühn T, Floegel A, Sookthai D, Johnson T, Rolle-Kampczyk U. Otto W, et al. Higher plasma levels of lysophosphatidylcholine 18: 0 are related to a lower risk of common cancers in a prospective metabolomics study. BMC Med. 2016; 14(1): 1–9.

[211] Ross T, Jakubzig B, Grundmann M, Massing U, Kostenis E, Schlesinger M, et al. The molecular mechanism by which saturated lysophosphatidylcholine attenuates the metastatic capacity of melanoma cells. FEBS Open Bio. 2016; 6(12): 1297–1309.

[212] Yin M-z, Tan S, Li X, Hou Y, Cao G, Li K, et al. Identification of phosphatidylcholine and lysophosphatidylcholine as novel biomarkers for cervical cancers in a prospective cohort study. Tumour Biol. 2016; 37: 5485–5492.

[213] Priolo C, Ricoult SJ, Khabibullin D, Filippakis H, Yu J, Manning BD, et al. Tuberous sclerosis complex 2 loss increases lysophosphatidylcholine synthesis in lymphangioleiomyomatosis. Am J Respir Cell Mol Biol. 2015; 53(1): 33–41.

[214] Shimizu R, Kanno K, Sugiyama A, Ohata H, Araki A, Kishikawa N, et al. Cholangiocyte senescence caused by lysophosphatidylcholine as a potential implication in carcinogenesis. J Hepatobiliary Pancreat Sci. 2015; 22(9): 675–682.

[215] Matsuda A, Yamada M, Matsumoto S, Sakurazawa N, Yamada T, Matsutani T, et al. Lysophosphatidylcholine as a predictor of postoperative complications after colorectal cancer surgery. Surg Today. 2018; 48: 936–943.

[216] Goto T, Terada N, Inoue T, Kobayashi T, Nakayama K, Okada Y, et al. Decreased expression of lysophosphatidylcholine (16:0/OH) in high resolution imaging mass spectrometry independently predicts biochemical recurrence after surgical treatment for prostate cancer. Prostate. 2015; 75(16): 1821–1830.

[217] Jantscheff P, Schlesinger M, Fritzsche J, Taylor LA, Graeser R, Kirfel G, et al. Lysophosphatidylcholine pretreatment reduces VLA-4 and P-Selectin–mediated B16. F10 melanoma cell adhesion in vitro and inhibits metastasis-like lung invasion in vivo. Mol Cancer Ther. 2011; 10(1): 186–197.

[218] Raynor A, Jantscheff P, Ross T, Schlesinger M, Wilde M, Haasis S, et al. Saturated and mono-unsaturated lysophosphatidylcholine metabolism in tumour cells: a potential therapeutic target for preventing metastases. Lipids Health Dis. 2015; 14(1): 1–15.

[219] Gaetano CG, Samadi N, Tomsig JL, Macdonald TL, Lynch KR, Brindley DN. Inhibition of autotaxin production or activity blocks lysophosphatidylcholine-induced migration of human breast cancer and melanoma cells. Mol Carcinog. 2009; 48(9): 801–809.

[220] Rapaport E. Treatment of human tumor cells with ADP or ATP yields arrest of growth in the S phase of the cell cycle. J Cell Physiol. 1983; 114(3): 279–283.

[221] Shabbir M, Thompson C, Jarmulowiczc M, Mikhailidis D, Burnstock G. Effect of extracellular ATP on the growth of hormone-refractory prostate cancer in vivo. BJU Int. 2008; 102(1): 108–112.

[222] Haskell CM, Mendoza E, Pisters KMW, Fossella FV, Figlin RA. Phase II study of intravenous adenosine 5’-triphosphate in patients with previously untreated stage IIIB and Stage IV non-small cell lung cancer. Invest New Drugs. 1998; 16(1): 81–85.

[223] Zhou T, Damsky W, Weizman OE, McGeary MK, Hartmann KP, Rosen CE, et al. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Nature. 2020; 583(7817): 609–614.

[224] Aymeric L, Apetoh L, Ghiringhelli F, Tesniere A, Martins I, Kroemer G, et al. Tumor Cell Death and ATP Release Prime Dendritic Cells and Efficient Anticancer Immunity. Cancer Res. 2010; 70(3): 855–858.

[225] Chen Y, Yao Y, Sumi Y, Li A, To UK, Elkhal A, et al. Purinergic signaling: a fundamental mechanism in neutrophil activation. Sci Signal. 2010; 3(125): ra45.

[226] Aswad F, Kawamura H, Dennert G. High Sensitivity of CD4+CD25+ Regulatory T Cells to Extracellular Metabolites Nicotinamide Adenine Dinucleotide and ATP: A Role for P2×7 Receptors1. J Immunol. 2005; 175(5): 3075–3083.

[227] Ferrari D, La Sala A, Chiozzi P, Morelli A, Falzoni S, Girolomoni G, et al. The P2 purinergic receptors of human dendritic cells: identification and coupling to cytokine release. FASEB J. 2000; 14(15): 2466–2476.

[228] Trabanelli S, Očadlíková D, Gulinelli S, Curti A, Salvestrini V, de Paula Vieira R, et al. Extracellular ATP Exerts Opposite Effects on Activated and Regulatory CD4+ T Cells via Purinergic P2 Receptor Activation. J Immunol. 2012; 189(3): 1303–1310.

[229] Schumacher D, Strilic B, Sivaraj Kishor K, Wettschureck N, Offermanns S. Platelet-Derived Nucleotides Promote Tumor-Cell Transendothelial Migration and Metastasis via P2Y₂Receptor. Cancer Cell. 2013; 24(1): 130–137.

[230] Zhang Y, Gong LH, Zhang HQ, Du Q, You JF, Tian XX, et al. Extracellular ATP enhances in vitro invasion of prostate cancer cells by activating Rho GTPase and upregulating MMPs expression. Cancer Lett. 2010; 293(2): 189–197.

[231] Chakraborty P, Vaena SG, Thyagarajan K, Chatterjee S, Mehrotra S. Pro-Survival Lipid Sphingosine-1-Phosphate Metabolically Programs T Cells to Limit Anti-tumor Activity. Cell Rep. 2019; 28(7): 1879–1893.e7.

[232] Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov. 2007; 6(4): 273–286.

[233] Cartier A, Hla T. Sphingosine 1-phosphate: Lipid signaling in pathology and therapy. Science. 2019; 366(6463): eaar5551.

[234] Cartier A, Leigh T, Liu CH, Hla T. Endothelial sphingosine 1-phosphate receptors promote vascular normalization and antitumor therapy. Proc Natl Acad Sci U S A. 2020; 117(6): 3157–3166.

[235] Sciumè G, Soriani A, Piccoli M, Frati L, Santoni A, Bernardini G. CX3CR1/CX3CL1 axis negatively controls glioma cell invasion and is modulated by transforming growth factor-β1. Neuro Oncol. 2010; 12(7): 701–710.

[236] Erreni M, Solinas G, Brescia P, Osti D, Zunino F, Colombo P, et al. Human glioblastoma tumours and neural cancer stem cells express the chemokine CX3CL1 and its receptor CX3CR1. Eur J Cancer. 2010; 46(18): 3383–3392.

[237] Lee S, Latha K, Manyam G, Yang Y, Rao A, Rao G. Role of CX3CR1 signaling in malignant transformation of gliomas. Neuro Oncol. 2020; 22(10): 1463–1473.

[238] Tardáguila M, Mira E, García-Cabezas MA, Feijoo AM, Quintela-Fandino M. Azcoitia I, et al. CX3CL1 promotes breast cancer via transactivation of the EGF pathway. Cancer Res. 2013; 73(14): 4461–4473.

[239] Schmall A, Al-Tamari HM. Herold S, Kampschulte M, Weigert A, Wietelmann A, et al. Macrophage and cancer cell cross-talk via CCR2 and CX3CR1 is a fundamental mechanism driving lung cancer. Am J Respir Crit Care Med. 2015; 191(4): 437–447.

[240] Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007; 13(1): 54–61.

[241] Tesniere A, Schlemmer F, Boige V, Kepp O, Martins I, Ghiringhelli F, et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene. 2010; 29(4): 482–491.

[242] Peters LR, Raghavan M. Endoplasmic reticulum calcium depletion impacts chaperone secretion, innate immunity, and phagocytic uptake of cells. J Immunol. 2011; 187(2): 919–931.

[243] Panaretakis T, Kepp O, Brockmeier U, Tesniere A, Bjorklund AC, Chapman DC, et al. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. Embo j. 2009; 28(5): 578–590.

[244] Raghavan M, Wijeyesakere SJ, Peters LR, Del Cid N. Calreticulin in the immune system: ins and outs. Trends Immunol. 2013; 34(1): 13–21.

[245] Poon IKH, Lucas CD, Rossi AG, Ravichandran KS. Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol. 2014; 14(3): 166–180.

[246] Lillis AP, Van Duyn LB, Murphy-Ullrich JE. Strickland DK. LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol Rev. 2008; 88(3): 887–918.

[247] Feng M, Marjon KD, Zhu F, Weissman-Tsukamoto R. Levett A, Sullivan K, et al. Programmed cell removal by calreticulin in tissue homeostasis and cancer. Nat Commun. 2018; 9(1): 3194.

[248] Wijeyesakere SJ, Bedi SK, Huynh D, Raghavan M. The C-Terminal Acidic Region of Calreticulin Mediates Phosphatidylserine Binding and Apoptotic Cell Phagocytosis. J Immunol. 2016; 196(9): 3896–3909.

[249] Goicoechea S, Orr AW, Pallero MA, Eggleton P, Murphy-Ullrich JE. Thrombospondin mediates focal adhesion disassembly through interactions with cell surface calreticulin. J Biol Chem. 2000; 275(46): 36358–36368.

[250] Kishore U, Sontheimer RD, Sastry KN, Zaner KS, Zappi EG, Hughes GR, et al. Release of calreticulin from neutrophils may alter C1q-mediated immune functions. Biochem J. 1997; 322(Pt 2): 543–550.

[251] Ma Y, Adjemian S, Mattarollo Stephen R, Yamazaki T, Aymeric L, Yang H, et al. Anticancer Chemotherapy-Induced Intratumoral Recruitment and Differentiation of Antigen-Presenting Cells. Immunity. 2013; 38(4): 729–741.

[252] Sprooten J, Agostinis P, Garg AD. Type I interferons and dendritic cells in cancer immunotherapy. Int Rev Cell Mol Biol. 2019; 348: 217–262.

[253] Barkal AA, Brewer RE, Markovic M, Kowarsky M, Barkal SA, Zaro BW, et al. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature. 2019; 572(7769): 392–396.

[254] Wang J, Sun J, Liu LN, Flies DB, Nie X, Toki M, et al. Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy. Nat Med. 2019; 25(4): 656–666.

[255] Morrissey MA, Kern N, Vale RD. CD47 Ligation Repositions the Inhibitory Receptor SIRPA to Suppress Integrin Activation and Phagocytosis. Immunity. 2020; 53(2): 290–302.e6.

[256] Grinfeld J, Nangalia J, Baxter EJ, Wedge DC, Angelopoulos N, Cantrill R, et al. Classification and Personalized Prognosis in Myeloproliferative Neoplasms. N Engl J Med. 2018; 379(15): 1416–1430.

[257] Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013; 369(25): 2391–2405.

[258] Imai M, Araki M, Komatsu N. Somatic mutations of calreticulin in myeloproliferative neoplasms. Int J Hematol. 2017; 105(6): 743–747.

[259] Elf S, Abdelfattah NS, Baral AJ, Beeson D, Rivera JF, Ko A, et al. Defining the requirements for the pathogenic interaction between mutant calreticulin and MPL in MPN. Blood. 2018; 131(7): 782–786.

[260] Liu P, Zhao L, Loos F, Marty C, Xie W, Martins I, et al. Immunosuppression by Mutated Calreticulin Released from Malignant Cells. Mol Cell. 2020; 77(4): 748–760.e9.

[261] Chachoua I, Pecquet C, El-Khoury M. Nivarthi H, Albu R-I, Marty C, et al. Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants. Blood. 2016; 127(10): 1325–1335.

[262] Kroemer G, Zitvogel L. Subversion of calreticulin exposure as a strategy of immune escape. Cancer Cell. 2021; 39(4): 449–451.

[263] Lin H, Kryczek I, Li S, Green MD, Ali A, Hamasha R, et al. Stanniocalcin 1 is a phagocytosis checkpoint driving tumor immune resistance. Cancer Cell. 2021; 39(4): 480–493.e6.

[264] Dong Z, Davidson D, Pérez-Quintero Luis A, Kurosaki T, Swat W, Veillette A. The Adaptor SAP Controls NK Cell Activation by Regulating the Enzymes Vav-1 and SHIP-1 and by Enhancing Conjugates with Target Cells. Immunity. 2012; 36(6): 974–985.

[265] Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014; 41(1): 49–61.

[266] Beyer M, Mallmann MR, Xue J, Staratschek-Jox A. Vorholt D, Krebs W, et al. High-resolution transcriptome of human macrophages. PLoS One. 2012; 7(9): e45466.

[267] He Y, Bouwstra R, Wiersma VR, de Jong M, Jan Lourens H, Fehrmann R, et al. Cancer cell-expressed SLAMF7 is not required for CD47-mediated phagocytosis. Nat Commun. 2019; 10(1): 533.

[268] Lu Y, Huntoon K, Lee D, Wang Y, Ha J, Qie Y, et al. Immunological conversion of solid tumours using a bispecific nanobioconjugate for cancer immunotherapy. Nat Nanotechnol. 2022; 17(12): 1332–1341.

[269] Kikuchi J, Hori M, Iha H, Toyama-Sorimachi N. Hagiwara S, Kuroda Y, et al. Soluble SLAMF7 promotes the growth of myeloma cells via homophilic interaction with surface SLAMF7. Leukemia. 2020; 34(1): 180–195.

[270] Pazina T, James AM, Colby KB, Yang Y, Gale A, Jhatakia A, et al. Enhanced SLAMF7 Homotypic Interactions by Elotuzumab Improves NK Cell Killing of Multiple Myeloma. Cancer Immunol Res. 2019; 7(10): 1633–1646.

[271] Hsi ED, Steinle R, Balasa B, Szmania S, Draksharapu A, Shum BP, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res. 2008; 14(9): 2775–2784.

[272] Bournazos S, Wang TT, Dahan R, Maamary J, Ravetch JV. Signaling by Antibodies: Recent Progress. Annu Rev Immunol. 2017; 35(1): 285–311.

[273] Mimura Y, Katoh T, Saldova R, O’Flaherty R, Izumi T, Mimura-Kimura Y. et al. Glycosylation engineering of therapeutic IgG antibodies: challenges for the safety, functionality and efficacy. Protein Cell. 2018; 9(1): 47–62.

[274] Kaneko Y, Nimmerjahn F, Ravetch J. Anti-Inflammatory Activity of Immunoglobulin G Resulting from Fc Sialylation. Science. 2006; 313: 670–673.

[275] Lux A, Nimmerjahn F. Impact of differential glycosylation on IgG activity. Adv Exp Med Biol. 2011; 780: 113–124.

[276] Lee CH, Romain G, Yan W, Watanabe M, Charab W, Todorova B, et al. IgG Fc domains that bind C1q but not effector Fcγ receptors delineate the importance of complement-mediated effector functions. Nat Immunol. 2017; 18(8): 889–898.

[277] Kurdi AT, Glavey SV, Bezman NA, Jhatakia A, Guerriero JL, Manier S, et al. Antibody-Dependent Cellular Phagocytosis by Macrophages is a Novel Mechanism of Action of Elotuzumab. Mol Cancer Ther. 2018; 17(7): 1454–1463.

[278] Kamen L, Myneni S, Langsdorf C, Kho E, Ordonia B, Thakurta T, et al. A novel method for determining antibody-dependent cellular phagocytosis. J Immunol Methods. 2019; 468: 55–60.

[279] Pincetic A, Bournazos S, DiLillo DJ, Maamary J, Wang TT, Dahan R, et al. Type I and type II Fc receptors regulate innate and adaptive immunity. Nat Immunol. 2014; 15(8): 707–716.

[280] Regnault A, Lankar D, Lacabanne V, Rodriguez A, Théry C, Rescigno M, et al. Fcgamma receptor-mediated induction of dendritic cell maturation and major histocompatibility complex class I-restricted antigen presentation after immune complex internalization. J Exp Med. 1999; 189(2): 371–380.

[281] Dhodapkar KM, Krasovsky J, Williamson B, Dhodapkar MV. Antitumor monoclonal antibodies enhance cross-presentation ofcCellular antigens and the generation of myeloma-specific killer T cells by dendritic cells. J Exp Med. 2002; 195(1): 125–133.

[282] Schuurhuis DH, van Montfoort N, Ioan-Facsinay A. Jiawan R, Camps M, Nouta J, et al. Immune complex-loaded dendritic cells are superior to soluble immune complexes as antitumor vaccine. J Immunol. 2006; 176(8): 4573–4580.

[283] Diaz de Ståhl T, Heyman B. IgG2a-mediated enhancement of antibody responses is dependent on FcRgamma+ bone marrow-derived cells. Scand J Immunol. 2001; 54(5): 495–500.

[284] Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med. 2000; 6(4): 443–446.

[285] Uchida J, Hamaguchi Y, Oliver JA, Ravetch JV, Poe JC, Haas KM, et al. The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med. 2004; 199(12): 1659–1669.

[286] Bibeau F, Lopez-Crapez E. Di Fiore F, Thezenas S, Ychou M, Blanchard F, et al. Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol. 2009; 27(7): 1122–1129.

[287] Chow A, Schad S, Green MD, Hellmann MD, Allaj V, Ceglia N, et al. Tim-4(+) cavity-resident macrophages impair anti-tumor CD8(+) T cell immunity. Cancer Cell. 2021; 39(7): 973–988.e9.

[288] Yu J, Green MD, Li S, Sun Y, Journey SN, Choi JE, et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat Med. 2021; 27(1): 152–164.

[289] Wang W, Wu S, Cen Z, Zhang Y, Chen Y, Huang Y, et al. Mobilizing phospholipids on tumor plasma membrane implicates phosphatidylserine externalization blockade for cancer immunotherapy. Cell Rep. 2022; 41(5): 111582.

[290] Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med. 2009; 15(10): 1170–1178.

[291] Martins I, Tesniere A, Kepp O, Michaud M, Schlemmer F, Senovilla L, et al. Chemotherapy induces ATP release from tumor cells. Cell Cycle. 2009; 8(22): 3723–3728.

[292] Klysz DD, Fowler C, Malipatlolla M, Stuani L, Freitas KA, Chen Y, et al. Inosine induces stemness features in CAR-T cells and enhances potency. Cancer Cell. 2024; 42(2): 266–282.e8.

[293] Janneh AH, Kassir MF, Atilgan FC, Lee HG, Sheridan M, Oleinik N, et al. Crosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis. Cell Rep. 2022; 41(10): 111742.

[294] Gupta P, Kadamberi IP, Mittal S, Tsaih SW, George J, Kumar S, et al. Tumor Derived Extracellular Vesicles Drive T Cell Exhaustion in Tumor Microenvironment through Sphingosine Mediated Signaling and Impacting Immunotherapy Outcomes in Ovarian Cancer. Adv Sci (Weinh). 2022; 9(14): e2104452.

[295] Fucikova J, Moserova I, Truxova I, Hermanova I, Vancurova I, Partlova S, et al. High hydrostatic pressure induces immunogenic cell death in human tumor cells. Int J Cancer. 2014; 135(5): 1165–1177.

[296] De Ruysscher D, Niedermann G, Burnet NG, Siva S, Lee AWM, Hegi-Johnson F. Radiotherapy toxicity. Nat Rev Dis Primers. 2019; 5(1): 13.

[297] Zhuang Y, Liu K, He Q, Gu X, Jiang C, Wu J. Hypoxia signaling in cancer: Implications for therapeutic interventions. Med Comm (2020). 2023; 4(1): e203.

[298] Li W, Yang J, Luo L, Jiang M, Qin B, Yin H, et al. Targeting photodynamic and photothermal therapy to the endoplasmic reticulum enhances immunogenic cancer cell death. Nat Commun. 2019; 10(1): 3349.

[299] Duewell P, Steger A, Lohr H, Bourhis H, Hoelz H, Kirchleitner SV, et al. RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8(+) T cells. Cell Death Differ. 2014; 21(12): 1825–1837.

[300] Bian M, Fan R, Yang Z, Chen Y, Xu Z, Lu Y, et al. Pt(II)-NHC Complex Induces ROS-ERS-Related DAMP Balance to Harness Immunogenic Cell Death in Hepatocellular Carcinoma. J Med Chem. 2022; 65(3): 1848–1866.

[301] Lin AG, Xiang B, Merlino DJ, Baybutt TR, Sahu J, Fridman A, et al. Non-thermal plasma induces immunogenic cell death in vivo in murine CT26 colorectal tumors. Oncoimmunology. 2018; 7(9): e1484978.

[302] Nuccitelli R, McDaniel A, Anand S, Cha J, Mallon Z, Berridge JC, et al. Nano-Pulse Stimulation is a physical modality that can trigger immunogenic tumor cell death. J Immunother Cancer. 2017; 5: 32.

[303] Gogishvili T, Danhof S, Prommersberger S, Rydzek J, Schreder M, Brede C, et al. SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7+ normal lymphocytes. Blood. 2017; 130(26): 2838–2847.

[304] O’Neal J, Ritchey JK, Cooper ML, Niswonger J, Sofía González L, Street E, et al. CS1 CAR-T targeting the distal domain of CS1 (SLAMF7) shows efficacy in high tumor burden myeloma model despite fratricide of CD8+CS1 expressing CAR-T cells. Leukemia. 2022; 36(6): 1625–1634.

[305] Chen Y, Huang Y, Li Q, Luo Z, Zhang Z, Huang H, et al. Targeting Xkr8 via nanoparticle-mediated in situ co-delivery of siRNA and chemotherapy drugs for cancer immunochemotherapy. Nat Nanotechnol. 2023; 18(2): 193–204.

[306] Zhang F, Li R, Yang Y, Shi C, Shen Y, Lu C, et al. Specific Decrease in B-Cell-Derived Extracellular Vesicles Enhances Post-Chemotherapeutic CD8(+) T Cell Responses. Immunity. 2019; 50(3): 738–750.e7.

[307] Häusler SFM, Montalbán del Barrio I, Strohschein J, Anoop Chandran P, Engel JB, Hönig A, et al. Ectonucleotidases CD39 and CD73 on OvCA cells are potent adenosine-generating enzymes responsible for adenosine receptor 2A-dependent suppression of T cell function and NK cell cytotoxicity. Cancer Immunol Immunother. 2011; 60(10): 1405–1418.

[308] Schmitt M, Ceteci F, Gupta J, Pesic M, Böttger TW, Nicolas AM, et al. Colon tumour cell death causes mTOR dependence by paracrine P2×4 stimulation. Nature. 2022; 612(7939): 347–353.

[309] Gupta P, Kadamberi IP, Mittal S, Tsaih S-W, George J, Kumar S, et al. Tumor Derived Extracellular Vesicles Drive T Cell Exhaustion in Tumor Microenvironment through Sphingosine Mediated Signaling and Impacting Immunotherapy Outcomes in Ovarian Cancer. Adv Sci (Weinh). 2022; 9(14): e2104452.

[310] Yi L, Liang Y, Zhao Q, Wang H, Dong J. CX3CL1 Induces Vertebral Microvascular Barrier Dysfunction via the Src/P115-RhoGEF/ROCK Signaling Pathway. Front Cell Neurosci. 2020; 14: 96.

[311] Old EA, Nadkarni S, Grist J, Gentry C, Bevan S, Kim KW, et al. Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain. J Clin Invest. 2014; 124(5): 2023–2036.

[312] Fucikova J, Kepp O, Kasikova L, Petroni G, Yamazaki T, Liu P, et al. Detection of immunogenic cell death and its relevance for cancer therapy. Cell Death Dis. 2020; 11(11): 1013.

[313] Yu Z, Guo J, Hu M, Gao Y, Huang L. Icaritin exacerbates mitophagy and synergizes with doxorubicin to induce immunogenic cell death in hepatocellular carcinoma. Acs Nano. 2020; 14(4): 4816–4828.

[314] Mei K-C, Liao Y-P, Jiang J, Chiang M, Khazaieli M, Liu X, et al. Liposomal delivery of mitoxantrone and a cholesteryl indoximod prodrug provides effective chemo-immunotherapy in multiple solid tumors. ACS nano. 2020; 14(10): 13343–13366.

[315] Kwon S, Meng F, Tamam H, Gadalla HH, Wang J, Dong B, et al. Systemic Delivery of Paclitaxel by Find-Me Nanoparticles Activates Antitumor Immunity and Eliminates Tumors. ACS Nano. 2024; 18(4): 3681–3698.

[316] Sarkar A, Novohradsky V, Maji M, Babu T, Markova L, Kostrhunova H, et al. Multitargeting Prodrugs that Release Oxaliplatin, Doxorubicin and Gemcitabine are Potent Inhibitors of Tumor Growth and Effective Inducers of Immunogenic Cell Death. Angew Chem Int Ed Engl. 2023; 62(42): e202310774.

[317] Dudek AM, Garg AD, Krysko DV, De Ruysscher D, Agostinis P. Inducers of immunogenic cancer cell death. Cytokine Growth Factor Rev. 2013; 24(4): 319–333.

[318] Nawrocki ST, Carew JS, Dunner K, Jr., Boise LH, Chiao PJ, Huang P, et al. Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. Cancer Res. 2005; 65(24): 11510–11519.

[319] Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003; 3(5): 330–338.

[320] Liu X, Feng Z, Wang C, Su Q, Song H, Zhang C, et al. Co-localized delivery of nanomedicine and nanovaccine augments the postoperative cancer immunotherapy by amplifying T-cell responses. Biomaterials. 2020; 230: 119649.

[321] Diederich M, Muller F, Cerella C. Cardiac glycosides: From molecular targets to immunogenic cell death. Biochem Pharmacol. 2017; 125: 1–11.

[322] Dudek-Perić AM, Ferreira GB, Muchowicz A, Wouters J, Prada N, Martin S, et al. Antitumor Immunity Triggered by Melphalan Is Potentiated by Melanoma Cell Surface–Associated Calreticulin. Cancer Res. 2015; 75(8): 1603–1614.

[323] Liu Z, Zhang HM, Yuan J, Ye X, Taylor GA, Yang D. The immunity-related GTPase Irgm3 relieves endoplasmic reticulum stress response during coxsackievirus B3 infection via a PI3K/Akt dependent pathway. Cell Microbiol. 2012; 14(1): 133–146.

[324] Agostinis P, Berg K, Cengel KA, Foster TH, Girotti AW, Gollnick SO, et al. Photodynamic therapy of cancer: an update. CA Cancer J Clin. 2011; 61(4): 250–281.

[325] Kielbik M, Szulc-Kielbik I. Klink M. Calreticulin—Multifunctional Chaperone in Immunogenic Cell Death: Potential Significance as a Prognostic Biomarker in Ovarian Cancer Patients. Cells. 2021; 10(1): 130.

[326] Zhou H, Forveille S, Sauvat A, Yamazaki T, Senovilla L, Ma Y, et al. The oncolytic peptide LTX-315 triggers immunogenic cell death. Cell Death Dis. 2016; 7(3): e2134.

[327] Pasquereau-Kotula E, Habault J, Kroemer G, Poyet JL. The anticancer peptide RT53 induces immunogenic cell death. PLoS One. 2018; 13(8): e0201220.

[328] Chen Z, Liu L, Liang R, Luo Z, He H, Wu Z, et al. Bioinspired Hybrid Protein Oxygen Nanocarrier Amplified Photodynamic Therapy for Eliciting Anti-tumor Immunity and Abscopal Effect. ACS Nano. 2018; 12(8): 8633–8645.

[329] Raines LN, Zhao H, Wang Y, Chen HY, Gallart-Ayala H. Hsueh PC, et al. PERK is a critical metabolic hub for immunosuppressive function in macrophages. Nat Immunol. 2022; 23(3): 431–445.

[330] Sun D, Cao M, Li H, He S, Chen W. Cancer burden and trends in China: A review and comparison with Japan and South Korea. Chin J Cancer Res. 2020; 32(2): 129–139.

[331] Zhou J, Tang Z, Gao S, Li C, Feng Y, Zhou X. Tumor-Associated Macrophages: Recent Insights and Therapies. Front Oncol. 2020; 10: 188.

[332] Lin W-D, Fan T-C, Hung JT, Yeo H-L, Wang S-H. Kuo C-W, et al. Sialylation of CD55 by ST3GAL1 Facilitates Immune Evasion in Cancer. Cancer Immunol Res. 2021; 9(1): 113–122.

[333] Tai Y-T, Dillon M, Song W, Leiba M, Li X-F, Burger P, et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood. 2008; 112(4): 1329–1337.

[334] Barnhart BC, Quigley M. Role of Fc-FcγR interactions in the antitumor activity of therapeutic antibodies. Immunol Cell Biol. 2017; 95(4): 340–346.

[335] Olafsen T, Kenanova VE, Wu AM. Tunable pharmacokinetics: modifying the in vivo half-life of antibodies by directed mutagenesis of the Fc fragment. Nat Protoc. 2006; 1(4): 2048–2060.

[336] Wu AM, Tan GJ, Sherman MA, Clarke P, Olafsen T, Forman SJ, et al. Multimerization of a chimeric anti-CD20 single-chain Fv-Fc fusion protein is mediated through variable domain exchange. Protein Eng. 2001; 14(12): 1025–1033.

[337] Weng WK, Negrin RS, Lavori P, Horning SJ. Immunoglobulin G Fc receptor FcgammaRIIIa 158 V/F polymorphism correlates with rituximab-induced neutropenia after autologous transplantation in patients with non-Hodgkin’s lymphoma. J Clin Oncol. 2010; 28(2): 279–284.

[338] Dooling LJ, Andrechak JC, Hayes BH, Kadu S, Zhang W, Pan R, et al. Cooperative phagocytosis of solid tumours by macrophages triggers durable anti-tumour responses. Nat Biomed Eng. 2023; 7(9): 1081–1096.

[339] Veillette A, Chen J. SIRPα–CD47 immune checkpoint blockade in anticancer therapy. Trends Immunol. 2018; 39(3): 173–184.

[340] Logtenberg ME, Scheeren FA, Schumacher TN. The CD47-SIRPα immune checkpoint. Immunity. 2020; 52(5): 742–752.

[341] Eladl E, Tremblay-LeMay R. Rastgoo N, Musani R, Chen W, Liu A, et al. Role of CD47 in hematological malignancies. J Hematol Oncol. 2020; 13: 1–14.

[342] Barkal AA, Weiskopf K, Kao KS, Gordon SR, Rosental B, Yiu YY, et al. Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nat Immunol. 2018; 19(1): 76–84.

[343] Zhao J, Zhong S, Niu X, Jiang J, Zhang R, Li Q. The MHC class I-LILRB1 signalling axis as a promising target in cancer therapy. Scand J Immunol. 2019; 90(5): e12804.

[344] Chen H-M, van der Touw W, Wang YS, Kang K, Mai S, Zhang J, et al. Blocking immunoinhibitory receptor LILRB2 reprograms tumor-associated myeloid cells and promotes antitumor immunity. J Clin Invest. 2018; 128(12): 5647–5662.

[345] Barkal AA, Brewer RE, Markovic M, Kowarsky M, Barkal SA, Zaro BW, et al. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature. 2019; 572(7769): 392–396.

[346] Li W, Wang F, Guo R, Bian Z, Song Y. Targeting macrophages in hematological malignancies: recent advances and future directions. J Hematol Oncol. 2022; 15(1): 110.

[347] Uger R, Johnson L. Blockade of the CD47-SIRPα axis: a promising approach for cancer immunotherapy. Expert Opin Biol Ther. 2020; 20(1): 5–8.

[348] Upton R, Banuelos A, Feng D, Biswas T, Kao K, McKenna K, et al. Combining CD47 blockade with trastuzumab eliminates HER2-positive breast cancer cells and overcomes trastuzumab tolerance. Proc Natl Acad Sci U S A. 2021; 118(29): e2026849118.

[349] Mehta A, Harb W, Xu C, Meng Y, Lee L, Yuan V, et al. Lemzoparlimab, a differentiated anti-cd47 antibody in combination with rituximab in relapsed and refractory non-Hodgkin’s lymphoma: initial clinical results. Blood. 2021; 138: 3542.

[350] Cao X, Wang Y, Zhang W, Zhong X, Gunes EG, Dang J, et al. Targeting macrophages for enhancing CD47 blockade–elicited lymphoma clearance and overcoming tumor-induced immunosuppression. Blood, J Am Soc Hematol. 2022; 139(22): 3290–3302.

[351] Theruvath J, Menard M, Smith BA, Linde MH, Coles GL, Dalton GN, et al. Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication. Nat Med. 2022; 28(2): 333–344.

[352] Liu J, Wang L, Zhao F, Tseng S, Narayanan C, Shura L, et al. Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PloS one. 2015; 10(9): e0137345.

[353] Fisher GA, Lakhani NJ, Eng C, Hecht JR, Bendell JC, Philip PA, et al. A phase Ib/II study of the anti-CD47 antibody magrolimab with cetuximab in solid tumor and colorectal cancer patients. J CLIN ONCOL. 2020; 38(4_suppl): 114.

[354] Advani R, Flinn I, Popplewell L, Forero A, Bartlett NL, Ghosh N, et al. CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin’s lymphoma. N Engl J Med. 2018; 379(18): 1711–1721.

[355] Goswami S, Anandhan S, Raychaudhuri D, Sharma P. Myeloid cell-targeted therapies for solid tumours. Nat Rev Immunol. 2023; 23(2): 106–120.

[356] Kamber RA, Nishiga Y, Morton B, Banuelos AM, Barkal AA, Vences-Catalán F, et al. Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis. Nature. 2021; 597(7877): 549–554.

[357] Li G, Jiang Y, Qin Y, Yuan S, Chen X. Comparing development strategies for PD1/PDL1-based immunotherapies. Nat Rev Drug Discov. 2022; 21(7): 484.

[358] Laba S, Mallett G, Amarnath S. The depths of PD-1 function within the tumor microenvironment beyond CD8(+) T cells. Semin Cancer Biol. 2022; 86(Pt 2): 1045–1055.

[359] Strauss L, Mahmoud MA, Weaver JD, Tijaro-Ovalle NM. Christofides A, Wang Q, et al. Targeted deletion of PD-1 in myeloid cells induces antitumor immunity. Sci Immunol. 2020; 5(43): eaay1863.

[360] Yang R, Sun L, Li C-F, Wang Y-H. Yao J, Li H, et al. Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nat Commun. 2021; 12(1): 832.

[361] Wang X, Wang G, Wang Z, Liu B, Han N, Li J, et al. PD-1-expressing B cells suppress CD4+ and CD8+ T cells via PD-1/PD-L1-dependent pathway. Mol Immunol. 2019; 109: 20–26.

[362] Hsu J, Hodgins JJ, Marathe M, Nicolai CJ, Bourgeois-Daigneault M-C, Trevino TN, et al. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J Clin Invest. 2018; 128(10): 4654–4668.

[363] Lim TS, Chew V, Sieow JL, Goh S, Yeong JP-S, Soon AL, et al. PD-1 expression on dendritic cells suppresses CD8+ T cell function and antitumor immunity. Oncoimmunology. 2016; 5(3): e1085146.

[364] Kleffel S, Posch C, Barthel SR, Mueller H, Schlapbach C, Guenova E, et al. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. Cell. 2015; 162(6): 1242–1256.

[365] He J, Hu Y, Hu M, Li B. Development of PD-1/PD-L1 Pathway in Tumor Immune Microenvironment and Treatment for Non-Small Cell Lung Cancer. Sci Rep. 2015; 5: 13110.

[366] Wu M, Huang Q, Xie Y, Wu X, Ma H, Zhang Y, et al. Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation. J Hematol Oncol. 2022; 15(1): 24.

[367] Reinke S, Bröckelmann PJ, Iaccarino I, Garcia-Marquez M. Borchmann S, Jochims F, et al. Tumor and microenvironment response but no cytotoxic T-cell activation in classic Hodgkin lymphoma treated with anti-PD1. Blood. 2020; 136(25): 2851–2863.

[368] Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med. 2016; 375(19): 1823–1833.

[369] Weinstock C, Khozin S, Suzman D, Zhang L, Tang S, Wahby S, et al. US Food and Drug Administration approval summary: atezolizumab for metastatic non–small cell lung cancer. Clin Cancer Res. 2017; 23(16): 4534–4539.

[370] Mok T, Wu Y-L, Sadowski S, Zhang J, Rangwala R, de Lima Lopes G. 481TiP Pembrolizumab (MK-3475) versus platinum-based chemotherapy for PD-L1+ non-small cell lung cancer (NSCLC): Randomized, open-label, phase 3 KEYNOTE-042 study. ANN ONCOL. 2015; 26: ix125.

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