Immune mediated support of metastasis: Implication for bone invasion

Abstract

Bone is a common organ affected by metastasis in various advanced cancers, including lung, breast, prostate, colorectal, and melanoma. Once a patient is diagnosed with bone metastasis, the patient’s quality of life and overall survival are significantly reduced owing to a wide range of morbidities and the increasing difficulty of treatment. Many studies have shown that bone metastasis is closely related to bone microenvironment, especially bone immune microenvironment. However, the effects of various immune cells in the bone microenvironment on bone metastasis remain unclear. Here, we described the changes in various immune cells during bone metastasis and discussed their related mechanisms. Osteoblasts, adipocytes, and other non-immune cells closely related to bone metastasis were also included. This review also summarized the existing treatment methods and potential therapeutic targets, and provided insights for future studies of cancer bone metastasis.

Keywords

bone metastasis / bone microenvironment / cancer / immune cell / therapy

References

[1] Hofbauer LC, Rachner TD, Coleman RE, Jakob F. Endocrine aspects of bone metastases. Lancet Diabetes Endocrinol. 2014; 2(6): 500–512.

[2] Song H, Arredondo Carrera HM, Sprules A, Ji Y, Zhang T, He J, et al. C-terminal variants of the P2×7 receptor are associated with prostate cancer progression and bone metastasis -evidence from clinical and pre-clinical data. Cancer Commun (Lond). 2023; 43(3): 400–404.

[3] Invernizzi M, Kim J, Fusco N. Editorial: Quality of Life in Breast Cancer Patients and Survivors. Front Oncol. 2020; 10: 620574.

[4] Baek YH, Jeon HL, Oh IS, Yang H, Park J, Shin JY. Incidence of skeletal-related events in patients with breast or prostate cancer-induced bone metastasis or multiple myeloma: A 12-year longitudinal nationwide healthcare database study. Cancer Epidemiol. 2019; 61: 104–110.

[5] Spencer JA, Ferraro F, Roussakis E, Klein A, Wu J, Runnels JM, et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature. 2014; 508(7495): 269–273.

[6] Hiraga T. Hypoxic Microenvironment and Metastatic Bone Disease. Int J Mol Sci. 2018; 19(11): 3523.

[7] Yuan FL, Xu MH, Li X, Xinlong H, Fang W, Dong J. The Roles of Acidosis in Osteoclast Biology. Front Physiol. 2016; 7: 222.

[8] Arnett TR. Acidosis, hypoxia and bone. Arch Biochem Biophys. 2010; 503(1): 103–109.

[9] Santos-de-Frutos K, Djouder N. When dormancy fuels tumour relapse. Commun Biol. 2021; 4(1): 747.

[10] Zhang Y, Liang J, Liu P, Wang Q, Liu L, Zhao H. The RANK/RANKL/OPG system and tumor bone metastasis: Potential mechanisms and therapeutic strategies. Front Endocrinol (Lausanne). 2022; 13: 1063815.

[11] Zhang X. Interactions between cancer cells and bone microenvironment promote bone metastasis in prostate cancer. Cancer Commun (Lond). 2019; 39(1): 76.

[12] Croucher PI, McDonald MM, Martin TJ. Bone metastasis: the importance of the neighbourhood. Nat Rev Cancer. 2016; 16(6): 373–386.

[13] Pastushenko I, Brisebarre A, Sifrim A, Fioramonti M, Revenco T, Boumahdi S, et al. Identification of the tumour transition states occurring during EMT. Nature. 2018; 556(7702): 463–468.

[14] Sistigu A, Di Modugno F, Manic G, Nisticò P. Deciphering the loop of epithelial-mesenchymal transition, inflammatory cytokines and cancer immunoediting. Cytokine Growth Factor Rev. 2017; 36: 67–77.

[15] Greten FR, Grivennikov SI. Inflammation and Cancer: Triggers, Mechanisms, and Consequences. Immunity. 2019; 51(1): 27–41.

[16] Fernandes R, Costa C, Fernandes R, Barros AN. Inflammation in Prostate Cancer: Exploring the Promising Role of Phenolic Compounds as an Innovative Therapeutic Approach. Biomedicines. 2023; 11(12): 3140.

[17] Hofbauer LC, Bozec A, Rauner M, Jakob F, Perner S, Pantel K. Novel approaches to target the microenvironment of bone metastasis. Nat Rev Clin Oncol. 2021; 18(8): 488–505.

[18] Del Conte A, De Carlo E, Bertoli E, Stanzione B, Revelant A, Bertola M, et al. Bone Metastasis and Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer (NSCLC): Microenvironment and Possible Clinical Implications. Int J Mol Sci. 2022; 23(12): 6832.

[19] Zhao E, Xu H, Wang L, Kryczek I, Wu K, Hu Y, et al. Bone marrow and the control of immunity. Cell Mol Immunol. 2012; 9(1): 11–19.

[20] Ponzetti M, Rucci N. Updates on Osteoimmunology: What’s New on the Cross-Talk Between Bone and Immune System. Front Endocrinol (Lausanne). 2019; 10: 236.

[21] Zhang W, Bado IL, Hu J, Wan YW, Wu L, Wang H, et al. The bone microenvironment invigorates metastatic seeds for further dissemination. Cell. 2021; 184(9): 2471–2486.e20.

[22] Juárez P, Guise TA. TGF-β in cancer and bone: implications for treatment of bone metastases. Bone. 2011; 48(1): 23–29.

[23] Singh T, Kaur V, Kumar M, Kaur P, Murthy RS, Rawal RK. The critical role of bisphosphonates to target bone cancer metastasis: an overview. J Drug Target. 2015; 23(1): 1–15.

[24] Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012; 379(9810): 39–46.

[25] Laccetti AL, Subudhi SK. Immunotherapy for metastatic prostate cancer: immuno-cold or the tip of the iceberg? Curr Opin Urol. 2017; 27(6): 566–571.

[26] Landi L, D’Incà F, Gelibter A, Chiari R, Grossi F, Delmonte A, et al. Bone metastases and immunotherapy in patients with advanced non-small-cell lung cancer. J Immunother Cancer. 2019; 7(1): 316.

[27] Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014; 41(1): 14–20.

[28] Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010; 141(1): 39–51.

[29] Yunna C, Mengru H, Lei W, Weidong C. Macrophage M1/M2 polarization. Eur J Pharmacol. 2020; 877: 173090.

[30] DeNardo DG, Ruffell B. Macrophages as regulators of tumour immunity and immunotherapy. Nat Rev Immunol. 2019; 19(6): 369–382.

[31] Azizi E, Carr AJ, Plitas G, Cornish AE, Konopacki C, Prabhakaran S, et al. Single-Cell Map of Diverse Immune Phenotypes in the Breast Tumor Microenvironment. Cell. 2018; 174(5): 1293–1308.e36.

[32] Zhai K, Huang Z, Huang Q, Tao W, Fang X, Zhang A, et al. Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells. Nat Cancer. 2021; 2(11): 1136–1151.

[33] Colegio OR, Chu N-Q, Szabo AL, Chu T, Rhebergen AM, Jairam V, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014; 513(7519): 559–563.

[34] Hibino S, Kawazoe T, Kasahara H, Itoh S, Ishimoto T, Sakata-Yanagimoto M. et al. Inflammation-Induced Tumorigenesis and Metastasis. Int J Mol Sci. 2021; 22(11): 5421.

[35] Bellavia D, Costa V, De Luca A, Cordaro A, Fini M, Giavaresi G, et al. The Binomial “Inflammation-Epigenetics” in Breast Cancer Progression and Bone Metastasis: IL-1β Actions Are Influenced by TET Inhibitor in MCF-7 Cell Line. Int J Mol Sci. 2022; 23(23): 15422.

[36] Magliacane Trotta S, Adinolfi A, D’Orsi L, Panico S, Mercadante G, Mehlen P, et al. Cancer-derived exosomal Alu RNA promotes colorectal cancer progression. Exp Mol Med. 2024; 56(3): 700–710.

[37] Pan Y, Yu Y, Wang X, Zhang T. Tumor-Associated Macrophages in Tumor Immunity. Front Immunol. 2020; 11: 583084.

[38] Munir MT, Kay MK, Kang MH, Rahman MM, Al-Harrasi A. Choudhury M, et al. Tumor-Associated Macrophages as Multifaceted Regulators of Breast Tumor Growth. Int J Mol Sci. 2021; 22(12): 6526.

[39] Yuan G, Huang Y, Yang ST, Ng A, Yang S. RGS12 inhibits the progression and metastasis of multiple myeloma by driving M1 macrophage polarization and activation in the bone marrow microenvironment. Cancer Commun (Lond). 2022; 42(1): 60–64.

[40] Lee JH, Kim HN, Kim KO, Jin WJ, Lee S, Kim HH, et al. CXCL10 promotes osteolytic bone metastasis by enhancing cancer outgrowth and osteoclastogenesis. Cancer Res. 2012; 72(13): 3175–3186.

[41] Shin SY, Nam JS, Lim Y, Lee YH. TNFα-exposed bone marrow-derived mesenchymal stem cells promote locomotion of MDA-MB-231 breast cancer cells through transcriptional activation of CXCR3 ligand chemokines. J Biol Chem. 2010; 285(40): 30731–30740.

[42] Midavaine É, Côté J, Sarret P. The multifaceted roles of the chemokines CCL2 and CXCL12 in osteophilic metastatic cancers. Cancer Metastasis Rev. 2021; 40(2): 427–445.

[43] Shen S, Zhang Y, Chen KG, Luo YL, Wang J. Cationic Polymeric Nanoparticle Delivering CCR2 siRNA to Inflammatory Monocytes for Tumor Microenvironment Modification and Cancer Therapy. Mol Pharm. 2018; 15(9): 3642–3653.

[44] Alsamraae M, Cook LM. Emerging roles for myeloid immune cells in bone metastasis. Cancer Metastasis Rev. 2021; 40(2): 413–425.

[45] Jiang P, Gao W, Ma T, Wang R, Piao Y, Dong X, et al. CD137 promotes bone metastasis of breast cancer by enhancing the migration and osteoclast differentiation of monocytes/macrophages. Theranostics. 2019; 9(10): 2950–2966.

[46] Leconet W, Chentouf M, du Manoir S, Chevalier C, Sirvent A, Aït-Arsa I, et al. Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis. Clin Cancer Res. 2017; 23(11): 2806–2816.

[47] Ma RY, Zhang H, Li XF, Zhang CB, Selli C, Tagliavini G, et al. Monocyte-derived macrophages promote breast cancer bone metastasis outgrowth. J Exp Med. 2020; 217(11): e20191820.

[48] Wu J, Yang H, Cheng J, Zhang L, Ke Y, Zhu Y, et al. Knockdown of milk-fat globule EGF factor-8 suppresses glioma progression in GL261 glioma cells by repressing microglial M2 polarization. J Cell Physiol. 2020; 235(11): 8679–8690.

[49] Soki FN, Koh AJ, Jones JD, Kim YW, Dai J, Keller ET, et al. Polarization of prostate cancer-associated macrophages is induced by milk fat globule-EGF factor 8 (MFG-E8)-mediated efferocytosis. J Biol Chem. 2014; 289(35): 24560–24572.

[50] Rutkowski MR, Stephen TL, Svoronos N, Allegrezza MJ, Tesone AJ, Perales-Puchalt A. et al. Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell. 2015; 27(1): 27–40.

[51] Roca H, Jones JD, Purica MC, Weidner S, Koh AJ, Kuo R, et al. Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone. J Clin Invest. 2018; 128(1): 248–266.

[52] Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009; 9(11): 798–809.

[53] Coscia M, Quaglino E, Iezzi M, Curcio C, Pantaleoni F, Riganti C, et al. Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway. J Cell Mol Med. 2010; 14(12): 2803–2815.

[54] Battafarano G, Rossi M, Marampon F, Del Fattore A. Cellular and Molecular Mediators of Bone Metastatic Lesions. Int J Mol Sci. 2018; 19(6): 1709.

[55] Huang Z, Zhang Z, Jiang Y, Zhang D, Chen J, Dong L, et al. Targeted delivery of oligonucleotides into tumor-associated macrophages for cancer immunotherapy. J Control Release. 2012; 158(2): 286–292.

[56] Ma S, Li X, Mai Y, Guo J, Zuo W, Yang J. Immunotherapeutic treatment of lung cancer and bone metastasis with a mPLA/mRNA tumor vaccine. Acta Biomater. 2023; 169: 489–499.

[57] Jiang J, Mei J, Yi S, Feng C, Ma Y, Liu Y, et al. Tumor associated macrophage and microbe: The potential targets of tumor vaccine delivery. Adv Drug Deliv Rev. 2022; 180: 114046.

[58] Ge YW, Liu XL, Yu DG, Zhu ZA, Ke QF, Mao YQ, et al. Graphene-modified CePO4 nanorods effectively treat breast cancer-induced bone metastases and regulate macrophage polarization to improve osteo-inductive ability. J Nanobiotechnology. 2021; 19(1): 11.

[59] Bliss SA, Sinha G, Sandiford OA, Williams LM, Engelberth DJ, Guiro K, et al. Mesenchymal Stem Cell-Derived Exosomes Stimulate Cycling Quiescence and Early Breast Cancer Dormancy in Bone Marrow. Cancer Res. 2016; 76(19): 5832–5844.

[60] Sosa MS, Bragado P, Aguirre-Ghiso JA. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer. 2014; 14(9): 611–622.

[61] Hosseini H, Obradović MMS, Hoffmann M, Harper KL, Sosa MS, Werner-Klein M. et al. Early dissemination seeds metastasis in breast cancer. Nature. 2016; 540(7634): 552–558.

[62] Walker ND, Elias M, Guiro K, Bhatia R, Greco SJ, Bryan M, et al. Exosomes from differentially activated macrophages influence dormancy or resurgence of breast cancer cells within bone marrow stroma. Cell Death Dis. 2019; 10(2): 59.

[63] Choi SH, Kim AR, Nam JK, Kim JM, Kim JY, Seo HR, et al. Tumour-vasculature development via endothelial-to-mesenchymal transition after radiotherapy controls CD44v6(+) cancer cell and macrophage polarization. Nat Commun. 2018; 9(1): 5108.

[64] Boyce BF. Advances in the regulation of osteoclasts and osteoclast functions. J Dent Res. 2013; 92(10): 860–867.

[65] Jacome-Galarza CE, Percin GI, Muller JT, Mass E, Lazarov T, Eitler J, et al. Developmental origin, functional maintenance and genetic rescue of osteoclasts. Nature. 2019; 568(7753): 541–545.

[66] Maurizi A, Rucci N. The Osteoclast in Bone Metastasis: Player and Target. Cancers (Basel). 2018; 10(7): 218.

[67] Kim JM, Lin C, Stavre Z, Greenblatt MB, Shim JH. Osteoblast-Osteoclast Communication and Bone Homeostasis. Cells. 2020; 9(9): 2073.

[68] Sun Y, Li J, Xie X, Gu F, Sui Z, Zhang K, et al. Macrophage-Osteoclast Associations: Origin, Polarization, and Subgroups. Front Immunol. 2021; 12: 778078.

[69] Kuo PL, Liao SH, Hung JY, Huang MS, Hsu YL. MicroRNA-33a functions as a bone metastasis suppressor in lung cancer by targeting parathyroid hormone related protein. Biochim Biophys Acta. 2013; 1830(6): 3756–3766.

[70] Esposito M, Mondal N, Greco TM, Wei Y, Spadazzi C, Lin SC, et al. Bone vascular niche E-selectin induces mesenchymal-epithelial transition and Wnt activation in cancer cells to promote bone metastasis. Nat Cell Biol. 2019; 21(5): 627–639.

[71] Celià-Terrassa T, Kang Y. Metastatic niche functions and therapeutic opportunities. Nat Cell Biol. 2018; 20(8): 868–877.

[72] Todd VM, Johnson RW. Hypoxia in bone metastasis and osteolysis. Cancer Lett. 2020; 489: 144–154.

[73] Yuan X, Qian N, Ling S, Li Y, Sun W, Li J, et al. Breast cancer exosomes contribute to pre-metastatic niche formation and promote bone metastasis of tumor cells. Theranostics. 2021; 11(3): 1429–1445.

[74] Yu L, Sui B, Fan W, Lei L, Zhou L, Yang L, et al. Exosomes derived from osteogenic tumor activate osteoclast differentiation and concurrently inhibit osteogenesis by transferring COL1A1-targeting miRNA-92a-1-5p. J Extracell Vesicles. 2021; 10(3): e12056.

[75] Wang K, Donnelly CR, Jiang C, Liao Y, Luo X, Tao X, et al. STING suppresses bone cancer pain via immune and neuronal modulation. Nat Commun. 2021; 12(1): 4558.

[76] Wang K, Gu Y, Liao Y, Bang S, Donnelly CR, Chen O, et al. PD-1 blockade inhibits osteoclast formation and murine bone cancer pain. J Clin Invest. 2020; 130(7): 3603–3620.

[77] Khan UA, Hashimi SM, Bakr MM, Forwood MR, Morrison NA. CCL2 and CCR2 are Essential for the Formation of Osteoclasts and Foreign Body Giant Cells. J Cell Biochem. 2016; 117(2): 382–389.

[78] Gao YJ, Cheng JK, Zeng Q, Xu ZZ, Decosterd I, Xu X, et al. Selective inhibition of JNK with a peptide inhibitor attenuates pain hypersensitivity and tumor growth in a mouse skin cancer pain model. Exp Neurol. 2009; 219(1): 146–155.

[79] Abbadie C, Bhangoo S, De Koninck Y, Malcangio M, Melik-Parsadaniantz S. White FA. Chemokines and pain mechanisms. Brain Res Rev. 2009; 60(1): 125–134.

[80] Xie RG, Gao YJ, Park CK, Lu N, Luo C, Wang WT, et al. Spinal CCL2 Promotes Central Sensitization, Long-Term Potentiation. and Inflammatory Pain via CCR2: Further Insights into Molecular, Synaptic, and Cellular Mechanisms. Neurosci Bull. 2018; 34(1): 13–21.

[81] Yue Z, Niu X, Yuan Z, Qin Q, Jiang W, He L, et al. RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis. J Clin Invest. 2022; 132(2): e144579.

[82] Zeeuwen PL, Cheng T, Schalkwijk J. The biology of cystatin M/E and its cognate target proteases. J Invest Dermatol. 2009; 129(6): 1327–1338.

[83] Jin L, Zhang Y, Li H, Yao L, Fu D, Yao X, et al. Differential secretome analysis reveals CST6 as a suppressor of breast cancer bone metastasis. Cell Res. 2012; 22(9): 1356–1373.

[84] Rivenbark AG, Jones WD, Coleman WB. DNA methylation-dependent silencing of CST6 in human breast cancer cell lines. Lab Invest. 2006; 86(12): 1233–1242.

[85] Li X, Liang Y, Lian C, Peng F, Xiao Y, He Y, et al. CST6 protein and peptides inhibit breast cancer bone metastasis by suppressing CTSB activity and osteoclastogenesis. Theranostics. 2021; 11(20): 9821–9832.

[86] Cocucci E, Meldolesi J. Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol. 2015; 25(6): 364–372.

[87] Savci-Heijink CD, Halfwerk H, Hooijer GK, Horlings HM, Wesseling J, van de Vijver MJ. Retrospective analysis of metastatic behaviour of breast cancer subtypes. Breast Cancer Res Treat. 2015; 150(3): 547–557.

[88] Ouchida M, Kanzaki H, Ito S, Hanafusa H, Jitsumori Y, Tamaru S, et al. Novel direct targets of miR-19a identified in breast cancer cells by a quantitative proteomic approach. PLoS One. 2012; 7(8): e44095.

[89] Wu K, Feng J, Lyu F, Xing F, Sharma S, Liu Y, et al. Exosomal miR-19a and IBSP cooperate to induce osteolytic bone metastasis of estrogen receptor-positive breast cancer. Nat Commun. 2021; 12(1): 5196.

[90] Kang Y. Dissecting Tumor-Stromal Interactions in Breast Cancer Bone Metastasis. Endocrinol Metab (Seoul). 2016; 31(2): 206–212.

[91] Fournier PG, Juárez P, Jiang G, Clines GA, Niewolna M, Kim HS, et al. The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone. Cancer Cell. 2015; 27(6): 809–821.

[92] Sethi N, Dai X, Winter CG, Kang Y. Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell. 2011; 19(2): 192–205.

[93] Javelaud D, Mohammad KS, McKenna CR, Fournier P, Luciani F, Niewolna M, et al. Stable overexpression of Smad7 in human melanoma cells impairs bone metastasis. Cancer Res. 2007; 67(5): 2317–2324.

[94] Mohammad KS, Javelaud D, Fournier PG, Niewolna M, McKenna CR, Peng XH, et al. TGF-beta-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases. Cancer Res. 2011; 71(1): 175–184.

[95] Danielpour D. Advances and Challenges in Targeting TGF-β Isoforms for Therapeutic Intervention of Cancer: A Mechanism-Based Perspective. Pharmaceuticals (Basel). 2024; 17(4): 533.

[96] Kang J, La Manna F, Bonollo F, Sampson N, Alberts IL, Mingels C, et al. Tumor microenvironment mechanisms and bone metastatic disease progression of prostate cancer. Cancer Lett. 2022; 530: 156–169.

[97] Özdemir BC, Hensel J, Secondini C, Wetterwald A, Schwaninger R, Fleischmann A, et al. The molecular signature of the stroma response in prostate cancer-induced osteoblastic bone metastasis highlights expansion of hematopoietic and prostate epithelial stem cell niches. PLoS One. 2014; 9(12): e114530.

[98] Lin SC, Yu-Lee LY. Lin SH. Osteoblastic Factors in Prostate Cancer Bone Metastasis. Curr Osteoporos Rep. 2018; 16(6): 642–647.

[99] Keller ET, Brown J. Prostate cancer bone metastases promote both osteolytic and osteoblastic activity. J Cell Biochem. 2004; 91(4): 718–729.

[100] Abe E, Yamamoto M, Taguchi Y, Lecka-Czernik B. O’Brien CA, Economides AN, et al. Essential requirement of BMPs-2/4 for both osteoblast and osteoclast formation in murine bone marrow cultures from adult mice: antagonism by noggin. J Bone Miner Res. 2000; 15(4): 663–673.

[101] Lawson MA, McDonald MM, Kovacic N, Hua Khoo W, Terry RL, Down J, et al. Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche. Nat Commun. 2015; 6: 8983.

[102] Kan C, Vargas G, Pape FL, Clézardin P. Cancer Cell Colonisation in the Bone Microenvironment. Int J Mol Sci. 2016; 17(10): 1674.

[103] Price TT, Burness ML, Sivan A, Warner MJ, Cheng R, Lee CH, et al. Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone. Sci Transl Med. 2016; 8(340): 340ra73.

[104] Shen Y, Lv Y. Dual targeted zeolitic imidazolate framework nanoparticles for treating metastatic breast cancer and inhibiting bone destruction. Colloids Surf B Biointerfaces. 2022; 219: 112826.

[105] Veglia F, Gabrilovich DI. Dendritic cells in cancer: the role revisited. Curr Opin Immunol. 2017; 45: 43–51.

[106] Wooster AL, Girgis LH, Brazeale H, Anderson TS, Wood LM, Lowe DB. Dendritic cell vaccine therapy for colorectal cancer. Pharmacol Res. 2021; 164: 105374.

[107] Zong J, Keskinov AA, Shurin GV, Shurin MR. Tumor-derived factors modulating dendritic cell function. Cancer Immunol Immunother. 2016; 65(7): 821–833.

[108] Brown RD, Pope B, Murray A, Esdale W, Sze DM, Gibson J, et al. Dendritic cells from patients with myeloma are numerically normal but functionally defective as they fail to up-regulate CD80 (B7-1) expression after huCD40LT stimulation because of inhibition by transforming growth factor-beta1 and interleukin-10. Blood. 2001; 98(10): 2992–2998.

[109] Tucci M, Stucci S, Strippoli S, Dammacco F, Silvestris F. Dendritic cells and malignant plasma cells: an alliance in multiple myeloma tumor progression? Oncologist. 2011; 16(7): 1040–1048.

[110] Nguyen-Pham TN, Lee YK, Lee HJ, Kim MH, Yang DH, Kim HJ, et al. Cellular immunotherapy using dendritic cells against multiple myeloma. Korean J Hematol. 2012; 47(1): 17–27.

[111] Schatz A, Mian BM. Current and emerging trends in prostate cancer immunotherapy. Asian J Androl. 2017; 21(1): 6–11.

[112] Fuessel S, Meye A, Schmitz M, Zastrow S, Linné C, Richter K, et al. Vaccination of hormone-refractory prostate cancer patients with peptide cocktail-loaded dendritic cells: results of a phase I clinical trial. Prostate. 2006; 66(8): 811–821.

[113] Jackson AM, Mulcahy LA, Zhu XW, O’Donnell D, Patel PM. Tumour-mediated disruption of dendritic cell function: inhibiting the MEK1/2-p44/42 axis restores IL-12 production and Th1-generation. Int J Cancer. 2008; 123(3): 623–632.

[114] Kraeber-Bodéré F, Campion L, Rousseau C, Bourdin S, Chatal JF, Resche I. Treatment of bone metastases of prostate cancer with strontium-89 chloride: efficacy in relation to the degree of bone involvement. Eur J Nucl Med. 2000; 27(10): 1487–1493.

[115] Liu J, Li J, Fan Y, Chang K, Yang X, Zhu W, et al. Concurrent dendritic cell vaccine and strontium-89 radiation therapy in the management of multiple bone metastases. Ir J Med Sci. 2015; 184(2): 457–461.

[116] De Silva NH, Akazawa T, Wijewardana V, Inoue N, Oyamada M, Ohta A, et al. Development of effective tumor immunotherapy using a novel dendritic cell-targeting Toll-like receptor ligand. PLoS One. 2017; 12(11): e0188738.

[117] Akazawa T, Ohashi T, Nakajima H, Nishizawa Y, Kodama K, Sugiura K, et al. Development of a dendritic cell-targeting lipopeptide as an immunoadjuvant that inhibits tumor growth without inducing local inflammation. Int J Cancer. 2014; 135(12): 2847–2856.

[118] Simons JW, Sacks N. Granulocyte-macrophage colony-stimulating factor-transduced allogeneic cancer cellular immunotherapy: the GVAX vaccine for prostate cancer. Urol Oncol. 2006; 24(5): 419–424.

[119] Stary G, Bangert C, Tauber M, Strohal R, Kopp T, Stingl G. Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells. J Exp Med. 2007; 204(6): 1441–1451.

[120] Drobits B, Holcmann M, Amberg N, Swiecki M, Grundtner R, Hammer M, et al. Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. J Clin Invest. 2012; 122(2): 575–585.

[121] Xiao W, Chan A, Waarts MR, Mishra T, Liu Y, Cai SF, et al. Plasmacytoid dendritic cell expansion defines a distinct subset of RUNX1-mutated acute myeloid leukemia. Blood. 2021; 137(10): 1377–1391.

[122] Sawant A, Hensel JA, Chanda D, Harris BA, Siegal GP, Maheshwari A, et al. Depletion of plasmacytoid dendritic cells inhibits tumor growth and prevents bone metastasis of breast cancer cells. J Immunol. 2012; 189(9): 4258–4265.

[123] Sax MJ, Gasch C, Athota VR, Freeman R, Rasighaemi P, Westcott DE, et al. Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer. Oncotarget. 2016; 7(51): 85437–85449.

[124] Fujimoto H, Sangai T, Ishii G, Ikehara A, Nagashima T, Miyazaki M, et al. Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer. 2009; 125(6): 1276–1284.

[125] Chaperot L, Perrot I, Jacob MC, Blanchard D, Salaun V, Deneys V, et al. Leukemic plasmacytoid dendritic cells share phenotypic and functional features with their normal counterparts. Eur J Immunol. 2004; 34(2): 418–426.

[126] Budhwar S, Verma P, Verma R, Rai S, Singh K. The Yin and Yang of Myeloid Derived Suppressor Cells. Front Immunol. 2018; 9: 2776.

[127] Ling Z, Yang C, Tan J, Dou C, Chen Y. Beyond immunosuppressive effects: dual roles of myeloid-derived suppressor cells in bone-related diseases. Cell Mol Life Sci. 2021; 78(23): 7161–7183.

[128] Nakamura K, Smyth MJ. Myeloid immunosuppression and immune checkpoints in the tumor microenvironment. Cell Mol Immunol. 2020; 17(1): 1–12.

[129] Hegde S, Leader AM, Merad M. MDSC: Markers, development, states, and unaddressed complexity. Immunity. 2021; 54(5): 875–884.

[130] Tesi RJ. MDSC; the Most Important Cell You Have Never Heard Of. Trends Pharmacol Sci. 2019; 40(1): 4–7.

[131] Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009; 9(3): 162–174.

[132] Hinshaw DC, Shevde LA. The Tumor Microenvironment Innately Modulates Cancer Progression. Cancer Res. 2019; 79(18): 4557–4566.

[133] Chen C, Huang R, Zhou J, Guo L, Xiang S. Formation of pre-metastatic bone niche in prostate cancer and regulation of traditional chinese medicine. Front Pharmacol. 2022; 13: 897942.

[134] Wang Y, Ding Y, Guo N, Wang S. MDSCs: Key Criminals of Tumor Pre-metastatic Niche Formation. Front Immunol. 2019; 10: 172.

[135] Zhao W, Xu Y, Xu J, Wu D, Zhao B, Yin Z, et al. Subsets of myeloid-derived suppressor cells in hepatocellular carcinoma express chemokines and chemokine receptors differentially. Int Immunopharmacol. 2015; 26(2): 314–321.

[136] Korbecki J, Simińska D, Kojder K, Grochans S, Gutowska I, Chlubek D, et al. Fractalkine/CX3CL1 in Neoplastic Processes. Int J Mol Sci. 2020; 21(10): 3723.

[137] Danilin S, Merkel AR, Johnson JR, Johnson RW, Edwards JR, Sterling JA. Myeloid-derived suppressor cells expand during breast cancer progression and promote tumor-induced bone destruction. Oncoimmunology. 2012; 1(9): 1484–1494.

[138] Van Valckenborgh E, Schouppe E, Movahedi K, De Bruyne E, Menu E, De Baetselier P, et al. Multiple myeloma induces the immunosuppressive capacity of distinct myeloid-derived suppressor cell subpopulations in the bone marrow. Leukemia. 2012; 26(11): 2424–2428.

[139] Wang G, Lu X, Dey P, Deng P, Wu CC, Jiang S, et al. Targeting YAP-Dependent MDSC Infiltration Impairs Tumor Progression. Cancer Discov. 2016; 6(1): 80–95.

[140] Wen J, Huang G, Liu S, Wan J, Wang X, Zhu Y, et al. Polymorphonuclear MDSCs are enriched in the stroma and expanded in metastases of prostate cancer. J Pathol Clin Res. 2020; 6(3): 171–177.

[141] Sawant A, Deshane J, Jules J, Lee CM, Harris BA, Feng X, et al. Myeloid-derived suppressor cells function as novel osteoclast progenitors enhancing bone loss in breast cancer. Cancer Res. 2013; 73(2): 672–682.

[142] Sawant A, Ponnazhagan S. Myeloid-derived suppressor cells as osteoclast progenitors: a novel target for controlling osteolytic bone metastasis. Cancer Res. 2013; 73(15): 4606–4610.

[143] Sawant A, Ponnazhagan S. Myeloid-derived suppressor cells as a novel target for the control of osteolytic bone disease. Oncoimmunology. 2013; 2(5): e24064.

[144] Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol. 2007; 179(2): 977–983.

[145] Rosales C, Lowell CA, Schnoor M, Uribe-Querol E. Neutrophils: Their Role in Innate and Adaptive Immunity 2017. J Immunol Res. 2017; 2017: 9748345.

[146] Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutrophil function: from mechanisms to disease. Annu Rev Immunol. 2012; 30: 459–489.

[147] Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013; 13(3): 159–175.

[148] Liang W, Ferrara N. The Complex Role of Neutrophils in Tumor Angiogenesis and Metastasis. Cancer Immunol Res. 2016; 4(2): 83–91.

[149] Mantovani A. The yin-yang of tumor-associated neutrophils. Cancer Cell. 2009; 16(3): 173–174.

[150] Piccard H, Muschel RJ, Opdenakker G. On the dual roles and polarized phenotypes of neutrophils in tumor development and progression. Crit Rev Oncol Hematol. 2012; 82(3): 296–309.

[151] Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell. 2009; 16(3): 183–194.

[152] Luca M, Huang S, Gershenwald JE, Singh RK, Reich R, Bar-Eli M. Expression of interleukin-8 by human melanoma cells up-regulates MMP-2 activity and increases tumor growth and metastasis. Am J Pathol. 1997; 151(4): 1105–1113.

[153] De Larco JE, Wuertz BR, Rosner KA, Erickson SA, Gamache DE, Manivel JC, et al. A potential role for interleukin-8 in the metastatic phenotype of breast carcinoma cells. Am J Pathol. 2001; 158(2): 639–646.

[154] Borregaard N, Sørensen OE, Theilgaard-Mönch K. Neutrophil granules: a library of innate immunity proteins. Trends Immunol. 2007; 28(8): 340–345.

[155] De Larco JE, Wuertz BR, Furcht LT. The potential role of neutrophils in promoting the metastatic phenotype of tumors releasing interleukin-8. Clin Cancer Res. 2004; 10(15): 4895–4900.

[156] Lin Q, Fang X, Liang G, Luo Q, Cen Y, Shi Y, et al. Silencing CTNND1 Mediates Triple-Negative Breast Cancer Bone Metastasis via Upregulating CXCR4/CXCL12 Axis and Neutrophils Infiltration in Bone. Cancers (Basel). 2021; 13(22): 5703.

[157] Kolonin MG, Sergeeva A, Staquicini DI, Smith TL, Tarleton CA, Molldrem JJ, et al. Interaction between Tumor Cell Surface Receptor RAGE and Proteinase 3 Mediates Prostate Cancer Metastasis to Bone. Cancer Res. 2017; 77(12): 3144–3150.

[158] Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, et al. Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature. 2000; 405(6784): 354–360.

[159] Yin C, Wang M, Wang Y, Lin Q, Lin K, Du H, et al. BHLHE22 drives the immunosuppressive bone tumor microenvironment and associated bone metastasis in prostate cancer. J Immunother Cancer. 2023; 11(3): e005532.

[160] Albrengues J, Shields MA, Ng D, Park CG, Ambrico A, Poindexter ME, et al. Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science. 2018; 361(6409): eaao4227.

[161] Koga Y, Matsuzaki A, Suminoe A, Hattori H, Hara T. Neutrophil-derived TNF-related apoptosis-inducing ligand (TRAIL): a novel mechanism of antitumor effect by neutrophils. Cancer Res. 2004; 64(3): 1037–1043.

[162] Costanzo-Garvey DL, Keeley T, Case AJ, Watson GF, Alsamraae M, Yu Y, et al. Neutrophils are mediators of metastatic prostate cancer progression in bone. Cancer Immunol Immunother. 2020; 69(6): 1113–1130.

[163] Ma X, Fan Y, Chen Z, Zhang Y, Wang S, Yu J. Blood biomarkers of bone metastasis in digestive tract malignant tumors. Future Oncol. 2021; 17(12): 1507–1518.

[164] Thio Q, Goudriaan WA, Janssen SJ, Paulino Pereira NR, Sciubba DM, Rosovksy RP, et al. Prognostic role of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in patients with bone metastases. Br J Cancer. 2018; 119(6): 737–743.

[165] Weller PF, Spencer LA. Functions of tissue-resident eosinophils. Nat Rev Immunol. 2017; 17(12): 746–760.

[166] Chusid MJ. Eosinophils: Friends or Foes? J Allergy Clin Immunol Pract. 2018; 6(5): 1439–1444.

[167] Grisaru-Tal S, Itan M, Grass DG, Torres-Roca J. Eschrich SA, Gordon Y, et al. Primary tumors from mucosal barrier organs drive unique eosinophil infiltration patterns and clinical associations. Oncoimmunology. 2020; 10(1): 1859732.

[168] Grisaru-Tal S, Rothenberg ME, Munitz A. Eosinophil-lymphocyte interactions in the tumor microenvironment and cancer immunotherapy. Nat Immunol. 2022; 23(9): 1309–1316.

[169] Zaynagetdinov R, Sherrill TP, Gleaves LA, McLoed AG, Saxon JA, Habermann AC, et al. Interleukin-5 facilitates lung metastasis by modulating the immune microenvironment. Cancer Res. 2015; 75(8): 1624–1634.

[170] Ikutani M, Yanagibashi T, Ogasawara M, Tsuneyama K, Yamamoto S, Hattori Y, et al. Identification of innate IL-5-producing cells and their role in lung eosinophil regulation and antitumor immunity. J Immunol. 2012; 188(2): 703–713.

[171] Li F, Du X, Lan F, Li N, Zhang C, Zhu C, et al. Eosinophilic inflammation promotes CCL6-dependent metastatic tumor growth. Sci Adv. 2021; 7(22): eabb5943.

[172] Miyake K, Ito J, Karasuyama H. Role of Basophils in a Broad Spectrum of Disorders. Front Immunol. 2022; 13: 902494.

[173] Liu Q, Luo D, Cai S, Li Q, Li X. Circulating basophil count as a prognostic marker of tumor aggressiveness and survival outcomes in colorectal cancer. Clin Transl Med. 2020; 9(1): 6.

[174] Wang C, Chen YG, Gao JL, Lyu GY, Su J, Zhang QI, et al. Low local blood perfusion, high white blood cell and high platelet count are associated with primary tumor growth and lung metastasis in a 4T1 mouse breast cancer metastasis model. Oncol Lett. 2015; 10(2): 754–760.

[175] Sektioglu IM, Carretero R, Bulbuc N, Bald T, Tüting T, Rudensky AY, et al. Basophils Promote Tumor Rejection via Chemotaxis and Infiltration of CD8+ T Cells. Cancer Res. 2017; 77(2): 291–302.

[176] Lakshmi Narendra B, Eshvendar Reddy K, Shantikumar S, Ramakrishna S. Immune system: a double-edged sword in cancer. Inflamm Res. 2013; 62(9): 823–834.

[177] Chen ML, Pittet MJ, Gorelik L, Flavell RA, Weissleder R, von Boehmer H, et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci U S A. 2005; 102(2): 419–424.

[178] Knutson KL, Disis ML, Salazar LG. CD4 regulatory T cells in human cancer pathogenesis. Cancer Immunol Immunother. 2007; 56(3): 271–285.

[179] Marshall EA, Ng KW, Kung SH, Conway EM, Martinez VD, Halvorsen EC, et al. Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis. Mol Cancer. 2016; 15(1): 67.

[180] Choi Y, Woo KM, Ko SH, Lee YJ, Park SJ, Kim HM, et al. Osteoclastogenesis is enhanced by activated B cells but suppressed by activated CD8(+) T cells. Eur J Immunol. 2001; 31(7): 2179–2188.

[181] Grcević D, Lukić IK, Kovacić N, Ivcević S, Katavić V, Marusić A. Activated T lymphocytes suppress osteoclastogenesis by diverting early monocyte/macrophage progenitor lineage commitment towards dendritic cell differentiation through down-regulation of receptor activator of nuclear factor-kappaB and c-Fos. Clin Exp Immunol. 2006; 146(1): 146–158.

[182] Monteiro AC, Leal AC, Gonçalves-Silva T, Mercadante AC, Kestelman F, Chaves SB, et al. T cells induce pre-metastatic osteolytic disease and help bone metastases establishment in a mouse model of metastatic breast cancer. PLoS One. 2013; 8(7): e68171.

[183] Monteiro AC, Bonomo A. CD8(+) T cells from experimental in situ breast carcinoma interfere with bone homeostasis. Bone. 2021; 150: 116014.

[184] Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006; 203(12): 2673–2682.

[185] Kfoury Y, Baryawno N, Severe N, Mei S, Gustafsson K, Hirz T, et al. Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment. Cancer Cell. 2021; 39(11): 1464–1478.e8.

[186] Santini D, Barni S, Intagliata S, Falcone A, Ferraù F, Galetta D, et al. Natural History of Non-Small-Cell Lung Cancer with Bone Metastases. Sci Rep. 2015; 5: 18670.

[187] Nigam R, Field M, Harris G, Barton M, Carolan M, Metcalfe P, et al. Automated detection, delineation and quantification of whole-body bone metastasis using FDG-PET/CT images. Phys Eng Sci Med. 2023; 46(2): 851–863.

[188] Liang H, Chen Q, Hu Z, Zhou L, Meng Q, Zhang T, et al. Siglec15 facilitates the progression of non-small cell lung cancer and is correlated with spinal metastasis. Ann Transl Med. 2022; 10(6): 281.

[189] Yang XR, Pi C, Zhang YC, Chen ZH, Zhang XC, Zhu DQ, et al. Heterogeneity in the immune microenvironment of bone metastasis in driver-positive non-small cell lung cancer. Mol Carcinog. 2023; 62(7): 1001–1008.

[190] Wu H, Xia L, Jia D, Zou H, Jin G, Qian W, et al. PD-L1(+) regulatory B cells act as a T cell suppressor in a PD-L1-dependent manner in melanoma patients with bone metastasis. Mol Immunol. 2020; 119: 83–91.

[191] Zuo H, Wan Y. Inhibition of myeloid PD-L1 suppresses osteoclastogenesis and cancer bone metastasis. Cancer Gene Ther. 2022; 29(10): 1342–1354.

[192] Barrueto L, Caminero F, Cash L, Makris C, Lamichhane P, Deshmukh RR. Resistance to Checkpoint Inhibition in Cancer Immunotherapy. Transl Oncol. 2020; 13(3): 100738.

[193] Mehdi A, Attias M, Arakelian A, Piccirillo CA, Szyf M, Rabbani SA. Co-Targeting Luminal B Breast Cancer with S-Adenosylmethionine and Immune Checkpoint Inhibitor Reduces Primary Tumor Growth and Progression, and Metastasis to Lungs and Bone. Cancers (Basel). 2022; 15(1): 48.

[194] Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK, et al. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Front Pharmacol. 2017; 8: 561.

[195] Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012; 12(4): 252–264.

[196] Xu Y, Mao Y, Lv Y, Tang W, Xu J. B cells in tumor metastasis: friend or foe? Int J Biol Sci. 2023; 19(8): 2382–2393.

[197] Helmink BA, Reddy SM, Gao J, Zhang S, Basar R, Thakur R, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature. 2020; 577(7791): 549–555.

[198] Perricone MA, Smith KA, Claussen KA, Plog MS, Hempel DM, Roberts BL, et al. Enhanced efficacy of melanoma vaccines in the absence of B lymphocytes. J Immunother. 2004; 27(4): 273–281.

[199] Meylan M, Petitprez F, Becht E, Bougoüin A, Pupier G, Calvez A, et al. Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer. Immunity. 2022; 55(3): 527–541.e5.

[200] Roato I, Brunetti G, Gorassini E, Grano M, Colucci S, Bonello L, et al. IL-7 up-regulates TNF-alpha-dependent osteoclastogenesis in patients affected by solid tumor. PLoS One. 2006; 1(1): e124.

[201] Gauthier L, Morel A, Anceriz N, Rossi B, Blanchard-Alvarez A. Grondin G, et al. Multifunctional Natural Killer Cell Engagers Targeting NKp46 Trigger Protective Tumor Immunity. Cell. 2019; 177(7): 1701–1713.e16.

[202] Liu S, Galat V, Galat Y, Lee YKA, Wainwright D, Wu J. NK cell-based cancer immunotherapy: from basic biology to clinical development. J Hematol Oncol. 2021; 14(1): 7.

[203] Li T, Yang Y, Hua X, Wang G, Liu W, Jia C, et al. Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett. 2012; 318(2): 154–161.

[204] Wu Y, Kuang DM, Pan WD, Wan YL, Lao XM, Wang D, et al. Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions. Hepatology. 2013; 57(3): 1107–1116.

[205] Pal S, Perrien DS, Yumoto T, Faccio R, Stoica A, Adams J, et al. The microbiome restrains melanoma bone growth by promoting intestinal NK and Th1 cell homing to bone. J Clin Invest. 2022; 132(12): e157340.

[206] Wu Q, Tian P, He D, Jia Z, He Y, Luo W, et al. SCUBE2 mediates bone metastasis of luminal breast cancer by modulating immune-suppressive osteoblastic niches. Cell Res. 2023; 33(6): 464–478.

[207] Miki T, Yano S, Hanibuchi M, Kanematsu T, Muguruma H, Sone S. Parathyroid hormone-related protein (PTHrP) is responsible for production of bone metastasis, but not visceral metastasis, by human small cell lung cancer SBC-5 cells in natural killer cell-depleted SCID mice. Int J Cancer. 2004; 108(4): 511–515.

[208] Miki T, Yano S, Hanibuchi M, Sone S. Bone metastasis model with multiorgan dissemination of human small-cell lung cancer (SBC-5) cells in natural killer cell-depleted SCID mice. Oncol Res. 2000; 12(5): 209–217.

[209] Zhang H, Yano S, Miki T, Goto H, Kanematsu T, Muguruma H, et al. A novel bisphosphonate minodronate (YM529) specifically inhibits osteolytic bone metastasis produced by human small-cell lung cancer cells in NK-cell depleted SCID mice. Clin Exp Metastasis. 2003; 20(2): 153–159.

[210] Rautela J, Baschuk N, Slaney CY, Jayatilleke KM, Xiao K, Bidwell BN, et al. Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer. Cancer Immunol Res. 2015; 3(11): 1207–1217.

[211] Deauvieau F, Ollion V, Doffin AC, Achard C, Fonteneau JF, Verronese E, et al. Human natural killer cells promote cross-presentation of tumor cell-derived antigens by dendritic cells. Int J Cancer. 2015; 136(5): 1085–1094.

[212] Zarrer J, Haider MT, Smit DJ, Taipaleenmäki H. Pathological Crosstalk between Metastatic Breast Cancer Cells and the Bone Microenvironment. Biomolecules. 2020; 10(2): 337.

[213] Conte M, Martucci M, Sandri M, Franceschi C, Salvioli S. The Dual Role of the Pervasive “Fattish” Tissue Remodeling With Age. Front Endocrinol (Lausanne). 2019; 10: 114.

[214] Wu Q, Li B, Sun S, Sun S. Unraveling Adipocytes and Cancer Links: Is There a Role for Senescence? Front Cell Dev Biol. 2020; 8: 282.

[215] Yao H, He S. Multi faceted role of cancer associated adipocytes in the tumor microenvironment (Review). Mol Med Rep. 2021; 24(6): 866.

[216] Herroon MK, Rajagurubandara E, Diedrich JD, Heath EI, Podgorski I. Adipocyte-activated oxidative and ER stress pathways promote tumor survival in bone via upregulation of Heme Oxygenase 1 and Survivin. Sci Rep. 2018; 8(1): 40.

[217] Diedrich JD, Rajagurubandara E, Herroon MK, Mahapatra G, Hüttemann M, Podgorski I. Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1α activation. Oncotarget. 2016; 7(40): 64854–64877.

[218] Hardaway AL, Herroon MK, Rajagurubandara E, Podgorski I. Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer. Clin Exp Metastasis. 2015; 32(4): 353–368.

[219] Sato S, Hiruma T, Koizumi M, Yoshihara M, Nakamura Y, Tadokoro H, et al. Bone marrow adipocytes induce cancer-associated fibroblasts and immune evasion, enhancing invasion and drug resistance. Cancer Sci. 2023; 114(6): 2674–2688.

[220] Dirat B, Bochet L, Dabek M, Daviaud D, Dauvillier S, Majed B, et al. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 2011; 71(7): 2455–2465.

[221] Fairfield H, Dudakovic A, Khatib CM, Farrell M, Costa S, Falank C, et al. Myeloma-Modified Adipocytes Exhibit Metabolic Dysfunction and a Senescence-Associated Secretory Phenotype. Cancer Res. 2021; 81(3): 634–647.

[222] Delgado-Calle J, Bellido T. Osteocytes and Skeletal Pathophysiology. Curr Mol Biol Rep. 2015; 1(4): 157–167.

[223] Grimaud E, Soubigou L, Couillaud S, Coipeau P, Moreau A, Passuti N, et al. Receptor activator of nuclear factor kappaB ligand (RANKL)/osteoprotegerin (OPG) ratio is increased in severe osteolysis. Am J Pathol. 2003; 163(5): 2021–2031.

[224] Wang H, Yu C, Gao X, Welte T, Muscarella AM, Tian L, et al. The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells. Cancer Cell. 2015; 27(2): 193–210.

[225] Jung Y, Wang J, Schneider A, Sun YX, Koh-Paige AJ. Osman NI, et al. Regulation of SDF-1 (CXCL12) production by osteoblasts; a possible mechanism for stem cell homing. Bone. 2006; 38(4): 497–508.

[226] Johnson RW, Finger EC, Olcina MM, Vilalta M, Aguilera T, Miao Y, et al. Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow. Nat Cell Biol. 2016; 18(10): 1078–1089.

[227] Decker AM, Jung Y, Cackowski FC, Yumoto K, Wang J, Taichman RS. Sympathetic Signaling Reactivates Quiescent Disseminated Prostate Cancer Cells in the Bone Marrow. Mol Cancer Res. 2017; 15(12): 1644–1655.

[228] Sosnoski DM, Norgard RJ, Grove CD, Foster SJ, Mastro AM. Dormancy and growth of metastatic breast cancer cells in a bone-like microenvironment. Clin Exp Metastasis. 2015; 32(4): 335–344.

[229] Hu W, Zhang L, Dong Y, Tian Z, Chen Y, Dong S. Tumour dormancy in inflammatory microenvironment: A promising therapeutic strategy for cancer-related bone metastasis. Cell Mol Life Sci. 2020; 77(24): 5149–5169.

[230] Dai R, Liu M, Xiang X, Xi Z, Xu H. Osteoblasts and osteoclasts: an important switch of tumour cell dormancy during bone metastasis. J Exp Clin Cancer Res. 2022; 41(1): 316.

[231] Wu AC, He Y, Broomfield A, Paatan NJ, Harrington BS, Tseng HW, et al. CD169(+) macrophages mediate pathological formation of woven bone in skeletal lesions of prostate cancer. J Pathol. 2016; 239(2): 218–230.

[232] Delgado-Calle J, Bellido T. The osteocyte as a signaling cell. Physiol Rev. 2022; 102(1): 379–410.

[233] Uda Y, Azab E, Sun N, Shi C, Pajevic PD. Osteocyte Mechanobiology. Curr Osteoporos Rep. 2017; 15(4): 318–325.

[234] Riquelme MA, Cardenas ER, Jiang JX. Osteocytes and Bone Metastasis. Front Endocrinol (Lausanne). 2020; 11: 567844.

[235] Myers TJ, Longobardi L, Willcockson H, Temple JD, Tagliafierro L, Ye P, et al. BMP2 Regulation of CXCL12 Cellular, Temporal, and Spatial Expression is Essential During Fracture Repair. J Bone Miner Res. 2015; 30(11): 2014–2027.

[236] Liu S, Fan Y, Chen A, Jalali A, Minami K, Ogawa K, et al. Osteocyte-Driven Downregulation of Snail Restrains Effects of Drd2 Inhibitors on Mammary Tumor Cells. Cancer Res. 2018; 78(14): 3865–3876.

[237] Zhou H, Zhang W, Li H, Xu F, Yinwang E, Xue Y, et al. Osteocyte mitochondria inhibit tumor development via STING-dependent antitumor immunity. Sci Adv. 2024; 10(3): eadi4298.

RIGHTS & PERMISSIONS

2024 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat-sen University Cancer Center.