Cytoskeleton governs exosome-mediated drug resistance under mechanical stress

Abstract

Drug resistance remains a critical obstacle in solid tumor therapy. While most studies have focused on chemical signaling within the tumor microenvironment, accumulating evidence has revealed that mechanical stress is a pivotal but underappreciated driver of drug resistance. Unlike previous reviews that have separately addressed mechanotransduction, exosome biology, and autophagy, this review proposes a vertically integrated framework - the “mechanical stress-cytoskeleton-exosomes-autophagy” axis - that connects these domains into a causal cascade from mechanical stress sensing to the dissemination of population-level resistance. Our central hypothesis is that cytoskeletal remodeling, driven by shear stress, matrix stiffness, and compressive stress, not only transduces mechanical signals intracellularly but also encodes these physical cues into exosomal cargo. These exosomes, in turn, transmit stress memory to recipient cells and trigger protective autophagy, thereby propagating drug-resistant phenotypes across heterogeneous tumor regions. We synthesize current evidence across biomechanics, vesicle trafficking, and stress biology and critically evaluate the intervention strategies that target each node of this axis. By reframing drug resistance as a mechanically propagated, exosome-mediated process, this review provides a new conceptual foundation and actionable directions for overcoming treatment failure.

Keywords

Drug resistance / exosomes / mechanical stress / cytoskeleton / tumor microenvironment / autophagy / intervention strategies

References

[1] Zhang H,Sun Y,Liu R.et al. The role of tumor microenvironment and signaling pathways in regulating breast cancer stem cells: Implications for therapy resistance and tumor recurrence Drug Resist Updat 2026 84 101315

[2] Fan H,Xu C,He S,Wang J,Zhu H,Shu K. Mechanical regulation of microenvironment remodeling in brain tumors: from mechanism to therapy J Neuroinflammation 2026 23 225 PMC13326260

[3] Papavassiliou KA,Basdra EK,Papavassiliou AG. The emerging promise of tumour mechanobiology in cancer treatment Eur J Cancer 2023 190 112938

[4] Alushin GM,Connolly SM,Njoku BC. Structural biophysics of cytoskeletal force transduction Annu Rev Cell Dev Biol 2026 Epub ahead of print

[5] Yang L,Akbarabadi P,Babashah S. Cancer-associated fibroblasts-derived exosomes in colorectal cancer progression: mechanism and therapeutic opportunities Biochim Biophys Acta Rev Cancer 2026 1881 189545

[6] Zhai H,Sun P,Bashir B.et al. Autophagy in thyroid cancer: Immune suppression and drug resistance Drug Resist Updat 2026 88 101437

[7] Huang M,Chen Y,Liang C.et al. Drug resistant cancer cells show increased nuclear mechanotransduction and mechanically targetable YAP-regulated vulnerability Biomaterials 2026 329 123920 PMC13179723

[8] Ji X,Zhang J,Qiu Y.et al. Visualization of mechanical force regulation of exosome secretion using high time-spatial resolution imaging Anal Chem 2025 97 1210 20

[9] Swartz MA,Lund AW. Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity Nat Rev Cancer 2012 12 210 9

[10] Zhu Y,Chen J,Chen C.et al. Deciphering mechanical cues in the microenvironment: from non-malignant settings to tumor progression Biomark Res 2025 13 11 PMC11755887

[11] Luo CW,Wu CC,Ch'ang HJ. Radiation sensitization of tumor cells induced by shear stress: the roles of integrins and FAK Biochim Biophys Acta 2014 1843 2129 37

[12] Dattachoudhury S,Sharma A,Sharma R,Pal S,Sukumar P,Jaganathan BG. Downregulation of PIEZO1 activity promotes breast cancer cell survival under shear stress by modulating β-catenin and BCL2 Cancer Res Commun 2026 6 1557 72

[13] Karasová M,Jobst M,Framke D.et al. Mechanical cues rewire lipid metabolism and support chemoresistance in epithelial ovarian cancer cell lines OVCAR3 and SKOV3 Cell Commun Signal 2025 23 193 PMC12016438

[14] Nath S,Pigula M,Khan AP.et al. Flow-induced shear stress confers resistance to carboplatin in an adherent three-dimensional model for ovarian cancer: a role for EGFR-targeted photoimmunotherapy informed by physical stress J Clin Med 2020 9 924 PMC7230263

[15] Feng T,Li B,Zhang C.et al. Fluid shear stress-mediated upregulated exosomal-IGF2 promotes hepatocellular carcinoma cell migration and metastasis Am J Cancer Res 2025 15 4570 85 PMC12616160

[16] Chen X,Xia Q,Sun N.et al. Shear stress enhances anoikis resistance of cancer cells through ROS and NO suppressed degeneration of Caveolin-1 Free Radic Biol Med 2022 193 95 107 PMC9561962

[17] Wang K,Wei Y,Liu W.et al. Mechanical stress-dependent autophagy component release via extracellular nanovesicles in tumor cells ACS Nano 2019 13 4589 602

[18] Yamashita T,Nagamoto S,Arai M,Kitayama S,Yano A,Higashi M. Metabolic and molecular mechanisms of gemcitabine resistance in urothelial carcinoma Cancers 2026 18 2126 PMC13359920

[19] Wright K,Ly T,Kriet M,Czirok A,Thomas SM. Cancer-associated fibroblasts: master tumor microenvironment modifiers Cancers 2023 15 1899 PMC10047485

[20] LeSavage BL,Zhang D,Huerta-López C.et al. Engineered matrices reveal stiffness-mediated chemoresistance in patient-derived pancreatic cancer organoids Nat Mater 2024 23 1138 49 PMC13098013

[21] Ren R,Zhang S,Peng Z.et al. Matrix stiffness regulates glucose-6-phosphate dehydrogenase expression to mediate sorafenib resistance in hepatocellular carcinoma through the ITGB1-PI3K/AKT pathway Cell Death Dis 2025 16 538 PMC12277399

[22] Yan J,Wu D,Zhu B.et al. 3D printed GelMA/HAMA based mechanical microenvironment boosted PDAC chemoresistance via NRF2-repressed ferroptosis Colloids Surf B Biointerfaces 2025 254 114816

[23] Wu B,Liu DA,Guan L.et al. Stiff matrix induces exosome secretion to promote tumour growth Nat Cell Biol 2023 25 415 24 PMC10351222

[24] Liu Z,Jin Q,Yan T,Wo Y,Liu H,Wang Y. Exosome-mediated transduction of mechanical force regulates prostate cancer migration via microRNA Biochem Biophys Rep 2022 31 101299 PMC9257336

[25] Röhrig F,Vorlová S,Hoffmann H.et al. VEGF-ablation therapy reduces drug delivery and therapeutic response in ECM-dense tumors Oncogene 2017 36 1 12 PMC5237662

[26] Biancacci I,De Santis D,Rama E.et al. Repurposing tamoxifen for tumor microenvironment priming and enhanced tumor-targeted drug delivery Adv Ther 2023 6 adtp PMC7616667

[27] Sun Y,Yin Z,Li S.et al. Losartan rewires the tumor-immune microenvironment and suppresses IGF-1 to overcome resistance to chemo-immunotherapy in ovarian cancer Br J Cancer 2024 131 1683 93 PMC11554678

[28] Burchard PR,Ruffolo LI,Ullman NA.et al. Pan-lysyl oxidase inhibition disrupts fibroinflammatory tumor stroma, rendering cholangiocarcinoma susceptible to chemotherapy Hepatol Commun 2024 8 e0502 PMC11299993

[29] Hou X,Shen Y,Huang B.et al. Losartan-based nanocomposite hydrogel overcomes chemo-immunotherapy resistance by remodeling tumor mechanical microenvironment J Nanobiotechnology 2024 22 667 PMC11523888

[30] Van Cutsem E,Tempero MA,Sigal D.et al. HALO 109-301 Investigators Randomized phase III trial of pegvorhyaluronidase alfa with nab-paclitaxel plus gemcitabine for patients with hyaluronan-high metastatic pancreatic adenocarcinoma J Clin Oncol 2020 38 3185 94 PMC7499614

[31] Stylianopoulos T,Martin JD,Chauhan VP.et al. Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors Proc Natl Acad Sci U S A 2012 109 15101 8 PMC3458380

[32] Safaei S,Sajed R,Shariftabrizi A.et al. Tumor matrix stiffness provides fertile soil for cancer stem cells Cancer Cell Int 2023 23 143 PMC10357884

[33] Rizzuti IF,Mascheroni P,Arcucci S.et al. Mechanical control of cell proliferation increases resistance to chemotherapeutic agents Phys Rev Lett 2020 125 128103

[34] Martino F,Perestrelo AR,Vinarský V,Pagliari S,Forte G. Cellular mechanotransduction: from tension to function Front Physiol 2018 9 824 PMC6041413

[35] Cascione M,De Matteis V,Toma CC,Pellegrino P,Leporatti S,Rinaldi R. Morphomechanical and structural changes induced by ROCK inhibitor in breast cancer cells Exp Cell Res 2017 360 303 9

[36] Shao B,Bu H,Li G,Kang D,Ju Q. Autophagy-dependent apoptosis induction by oridonin are mediated by ROS-dependent AMPK-mTOR-ULK1 pathway in colon cancer Am J Cancer Res 2025 15 1902 18 PMC12070090

[37] Yu W,Zhang C,Wang Y.et al. YAP 5-methylcytosine modification increases its mRNA stability and promotes the transcription of exosome secretion-related genes in lung adenocarcinoma Cancer Gene Ther 2023 30 149 62 PMC9842506

[38] Huang HM,Han CS,Cui SJ.et al. Mechanical force-promoted osteoclastic differentiation via periodontal ligament stem cell exosomal protein ANXA3 Stem Cell Reports 2022 17 1842 58 PMC9391435

[39] Yu Q,Guo K,Yang Y.et al. Fibroblast-derived exosomes induce macrophage pyroptosis to mediate orthodontic bone remodeling through the mtDNA/NLRP3 axis J Nanobiotechnology 2026 24 381 PMC13104472

[40] Huang J,Wei W,Kang F.et al. ANXA3, associated with YAP1 regulation, participates in the proliferation and chemoresistance of cervical cancer cells Genes Genomics 2023 45 1575 86

[41] Soliman BG,Tian P,Cui J,Kilian KA,Gooding JJ. Interfacial stress regulates plasticity and drug resistance at the breast cancer-host interface Adv Sci 2025 12 e09361 PMC12462989

[42] Cao M,Li Y,Su X.et al. Exosome-derived lnc-FAM72D-3 promotes lenvatinib resistance by remodeling hepatocellular carcinoma cytoskeleton via MBNL1/FAK axis Drug Resist Updat 2025 82 101271

[43] Momotyuk E,Ebrahim N,Shakirova K,Dashinimaev E. Role of the cytoskeleton in cellular reprogramming: effects of biophysical and biochemical factors Front Mol Biosci 2025 12 1538806 PMC11926148

[44] Xie N,Xiao C,Shu Q.et al. Cell response to mechanical microenvironment cues via Rho signaling: from mechanobiology to mechanomedicine Acta Biomater 2023 159 1 20

[45] van Niel G,D’Angelo G,Raposo G. Shedding light on the cell biology of extracellular vesicles Nat Rev Mol Cell Biol 2018 19 213 28

[46] Hessvik NP,Llorente A. Current knowledge on exosome biogenesis and release Cell Mol Life Sci 2018 75 193 208 PMC5756260

[47] Kalluri R,LeBleu VS. The biology, function, and biomedical applications of exosomes Science 2020 367 eaau6977 PMC7717626

[48] Yang S,Zhang X,Chen B.et al. Research progress on the interaction mechanisms and functions between exosomes and the cytoskeleton Front Cell Dev Biol 2026 14 1718115 PMC13180954

[49] Ding B,Yang S,Schaks M.et al. Structures reveal a key mechanism of WAVE regulatory complex activation by Rac1 GTPase Nat Commun 2022 13 5444 PMC9481577

[50] Latifkar A,Cerione RA,Antonyak MA. Probing the mechanisms of extracellular vesicle biogenesis and function in cancer Biochem Soc Trans 2018 46 1137 46 PMC6436556

[51] Sinha S,Hoshino D,Hong NH.et al. Cortactin promotes exosome secretion by controlling branched actin dynamics J Cell Biol 2016 214 197 213 PMC4949450

[52] Croisé P,Estay-Ahumada C,Gasman S,Ory S. Rho GTPases, phosphoinositides, and actin: a tripartite framework for efficient vesicular trafficking Small GTPases 2014 5 e29469 PMC4114633

[53] Song Z,Cui Y,Xin L.et al. Mechano-oncogenic cytoskeletal remodeling drives leukemic transformation with mitochondrial vesicle-mediated STING activation Cell Stem Cell 2025 32 581 97.e11

[54] Nagpal S,Swaminathan K,Beaudet D.et al. Optogenetic control of kinesin-1, -2, -3 and dynein reveals their specific roles in vesicular transport Cell Rep 2024 43 114649 PMC11416726

[55] Robinson BP,Bass NR,Bhakt P,Spiliotis ET. Septin-coated microtubules promote maturation of multivesicular bodies by inhibiting their motility J Cell Biol 2024 223 e202308049 PMC11046855

[56] Shi L,Jian Y,Li M,Hao T,Yang C,Wang X. Filamin FLN-2 promotes MVB biogenesis by mediating vesicle docking on the actin cytoskeleton J Cell Biol 2022 221 e202201020 PMC9115679

[57] Salas-Cortes L,Ye F,Tenza D.et al. Myosin Ib modulates the morphology and the protein transport within multi-vesicular sorting endosomes J Cell Sci 2005 118 4823 32

[58] Qiu X,Campos Y,van de Vlekkert D.et al. Distinct functions of dimeric and monomeric scaffold protein Alix in regulating F-actin assembly and loading of exosomal cargo J Biol Chem 2022 298 102425 PMC9531180

[59] Phuyal S,Farhan H. Multifaceted Rho GTPase signaling at the endomembranes Front Cell Dev Biol 2019 7 127 PMC6646525

[60] Asare-Werehene M,Nakka K,Reunov A.et al. The exosome-mediated autocrine and paracrine actions of plasma gelsolin in ovarian cancer chemoresistance Oncogene 2020 39 1600 16 PMC7018662

[61] Sun Q,Jin L,Dong S,Zhang L. LRRC59 promotes the progression of oral squamous cell carcinoma by interacting with SRP pathway components and enhancing the secretion of CKAP4-containing exosomes Heliyon 2024 10 e28083 PMC10963372

[62] Ma X,Liu K,Li J.et al. A non-canonical GTPase interaction enables ORP1L-Rab7-RILP complex formation and late endosome positioning J Biol Chem 2018 293 14155 64 PMC6130934

[63] Li H,De Santis MC,Tucci FA.et al. SH3BP5L triggers the RAB11A-regulated integrin recycling network implicated in breast cancer metastasis J Clin Invest 2026 136 e192705 PMC12867135

[64] Kurowska M,Goudin N,Nehme NT.et al. Terminal transport of lytic granules to the immune synapse is mediated by the kinesin-1/Slp3/Rab27a complex Blood 2012 119 3879 89 PMC3824283

[65] Serra-Marques A,Martin M,Katrukha EA.et al. Concerted action of kinesins KIF5B and KIF13B promotes efficient secretory vesicle transport to microtubule plus ends Elife 2020 9 e61302 PMC7710357

[66] Huang B,Deng X,Zhou G.et al. SYT4 binds to SNAP25 to facilitate exosomal secretion and prostate cancer enzalutamide resistance Cancer Sci 2024 115 2630 45 PMC11309949

[67] Mason JD,Marks E,Fan SJ.et al. Stress-induced Rab11a-exosomes induce amphiregulin-mediated cetuximab resistance in colorectal cancer J Extracell Vesicles 2024 13 e12465 PMC11184284

[68] Hussein NA,Malla S,Pasternak MA.et al. The role of endolysosomal trafficking in anticancer drug resistance Drug Resist Updat 2021 57 100769

[69] Shoji T,Shinojima A,Kishimoto T.et al. A PI(3,5)P₂/CHMP4B axis on lysosomes is essential for microautophagic degradation of STING Nat Commun 2026 17 4602 PMC13216264

[70] Yang Z,Li X,Lin Q.et al. Cortical actin depolymerisation in 3D cell culture enhances extracellular vesicle secretion and therapeutic effects J Extracell Vesicles 2025 14 e70109 PMC12326180

[71] Hinze C,Boucrot E. Local actin polymerization during endocytic carrier formation Biochem Soc Trans 2018 46 565 76

[72] Hoshino D,Kirkbride KC,Costello K.et al. Exosome secretion is enhanced by invadopodia and drives invasive behavior Cell Rep 2013 5 1159 68 PMC3873329

[73] Tian J,Zhang L,La X,Fan X,Li Z. MiR-769-5p of macrophage exosomes induced by GRP78 promotes stemness and chemoresistance in colorectal cancer Cell Death Dis 2025 16 156 PMC11882909

[74] Zhan Y,Zhou Z,Zhu Z.et al. Exosome-transmitted LUCAT1 promotes stemness transformation and chemoresistance in bladder cancer by binding to IGF2BP2 J Exp Clin Cancer Res 2025 44 80 PMC11874664

[75] Hu JH,Tang HN,Wang YH. Cancer-associated fibroblast exosome LINC00355 promotes epithelial-mesenchymal transition and chemoresistance in colorectal cancer through the miR-34b-5p/CRKL axis Cancer Gene Ther 2024 31 259 72

[76] Nakayama T,Kamiguchi H,Akagawa K. Syntaxin 1C, a soluble form of syntaxin, attenuates membrane recycling by destabilizing microtubules J Cell Sci 2012 125 817 30

[77] Ramirez C,Hauser AD,Vucic EA,Bar-Sagi D. Plasma membrane V-ATPase controls oncogenic RAS-induced macropinocytosis Nature 2019 576 477 81 PMC7048194

[78] Mulcahy LA,Pink RC,Carter DR. Routes and mechanisms of extracellular vesicle uptake J Extracell Vesicles 2014 3 24641 PMC4122821

[79] Zhao G,Zhang Y,Zhang H.et al. Tumor-derived exosomal tsRNA 3’tiRNA-AlaCGC in promoting fibroblast senescence and Galectin-9 secretion to induce immune tolerance in lung adenocarcinoma Cell Death Discov 2025 11 403 PMC12379295

[80] Han H,Li Y,Lin Z.et al. Exosomal miR-130a-3p confers cisplatin resistance in esophageal cancer by regulating ferroptosis via the suppression of METTL14-mediated m6A RNA methylation of FSP1 Int Immunopharmacol 2025 146 113804

[81] Abad E,Lyakhovich A. Movement of mitochondria with mutant DNA through extracellular vesicles helps cancer cells acquire chemoresistance ChemMedChem 2022 17 e202100642

[82] Mostafazadeh M,Samadi N,Kahroba H,Baradaran B,Haiaty S,Nouri M. Potential roles and prognostic significance of exosomes in cancer drug resistance Cell Biosci 2021 11 1 PMC7789218

[83] Panda SK,Sanchez-Pajares IR,Rehman A.et al. ER stress and/or ER-phagy in drug resistance? Three coincidences are proof Cell Commun Signal 2025 23 223 PMC12070796

[84] Hassanpour M,Rezabakhsh A,Rezaie J,Nouri M,Rahbarghazi R. Exosomal cargos modulate autophagy in recipient cells via different signaling pathways Cell Biosci 2020 10 92 PMC7395405

[85] Zubkova E,Kalinin A,Bolotskaya A,Beloglazova I,Menshikov M. Autophagy-dependent secretion: crosstalk between autophagy and exosome biogenesis Curr Issues Mol Biol 2024 46 2209 35 PMC10969067

[86] Liu J,Wu P,Li D.et al. Autophagy in cancer - functional plasticity, therapeutic paradox, and the road to precision modulation: a comprehensive review Mol Cancer 2026 Epub ahead of print

[87] Chen S,Guan JL. Tumor-promoting and -suppressive roles of autophagy in the same mouse model of BrafV600E-driven lung cancer Cancer Discov 2013 3 1225 7 PMC3832350

[88] Kaminskyy VO,Piskunova T,Zborovskaya IB,Tchevkina EM,Zhivotovsky B. Suppression of basal autophagy reduces lung cancer cell proliferation and enhances caspase-dependent and -independent apoptosis by stimulating ROS formation Autophagy 2012 8 1032 44 PMC3429541

[89] Goler-Baron V,Sladkevich I,Assaraf YG. Inhibition of the PI3K-Akt signaling pathway disrupts ABCG2-rich extracellular vesicles and overcomes multidrug resistance in breast cancer cells Biochem Pharmacol 2012 83 1340 8

[90] Visan KS,Lobb RJ,Moller A. The role of exosomes in the promotion of epithelial-to-mesenchymal transition and metastasis Front Biosci 2020 25 1022 57

[91] Guo H,Chitiprolu M,Roncevic L.et al. Atg5 Disassociates the V₁V₀-ATPase to promote exosome production and tumor metastasis independent of canonical macroautophagy Dev Cell 2017 43 716 30.e7

[92] Bhattacharya S,Pal K,Sharma AK.et al. GAIP interacting protein C-terminus regulates autophagy and exosome biogenesis of pancreatic cancer through metabolic pathways PLoS One 2014 9 e114409 PMC4255029

[93] Fan SJ,Kroeger B,Marie PP.et al. Glutamine deprivation alters the origin and function of cancer cell exosomes EMBO J 2020 39 e103009 PMC7429491

[94] Tan HWS,Sim AYL,Long YC. Glutamine metabolism regulates autophagy-dependent mTORC1 reactivation during amino acid starvation Nat Commun 2017 8 338 PMC5569045

[95] Zhang LH,Yang AJ,Wang M.et al. Enhanced autophagy reveals vulnerability of P-gp mediated epirubicin resistance in triple negative breast cancer cells Apoptosis 2016 21 473 88 PMC4915730

[96] Li Y,Yin Y,Zhang T.et al. A comprehensive landscape analysis of autophagy in cancer development and drug resistance Front Immunol 2024 15 1412781 PMC11381251

[97] Zhu S,Mao J,Zhang X.et al. CAF-derived exosomal lncRNA FAL1 promotes chemoresistance to oxaliplatin by regulating autophagy in colorectal cancer Dig Liver Dis 2024 56 330 42

[98] Guo H,Sadoul R,Gibbings D. Autophagy-independent effects of autophagy-related-5 (Atg5) on exosome production and metastasis Mol Cell Oncol 2018 5 e1445941 PMC6149948

[99] Backer JM. The regulation and function of Class III PI3Ks: novel roles for Vps34 Biochem J 2008 410 1 17

[100] Sasaki K,Tsuno NH,Sunami E.et al. Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells BMC Cancer 2010 10 370 PMC2914703

[101] Geng X,Li L,Luo Y.et al. Tumor cell derived lnc-FSD2-31:1 contributes to cancer-associated fibroblasts activation in pancreatic ductal adenocarcinoma progression through extracellular vesicles cargo MiR-4736 Adv Sci 2023 10 e2203324 PMC10074102

[102] Sung JS,Kang CW,Kang S.et al. ITGB4-mediated metabolic reprogramming of cancer-associated fibroblasts Oncogene 2020 39 664 76

[103] Kucharzewska P,Christianson HC,Welch JE.et al. Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development Proc Natl Acad Sci U S A 2013 110 7312 7 PMC3645587

[104] Liu DX,Li PP,Guo JP.et al. Exosomes derived from HBV-associated liver cancer promote chemoresistance by upregulating chaperone-mediated autophagy Oncol Lett 2019 17 323 31 PMC6313222

[105] Yuwen D,Ma Y,Wang D.et al. Prognostic role of circulating exosomal miR-425-3p for the response of NSCLC to platinum-based chemotherapy Cancer Epidemiol Biomarkers Prev 2019 28 163 73

[106] Kulkarni B,Gondaliya P,Kirave P.et al. Exosome-mediated delivery of miR-30a sensitize cisplatin-resistant variant of oral squamous carcinoma cells via modulating Beclin1 and Bcl2 Oncotarget 2020 11 1832 45 PMC7244014

[107] Pan Z,Zheng J,Zhang J.et al. A novel protein encoded by exosomal circATG4B induces oxaliplatin resistance in colorectal cancer by promoting autophagy Adv Sci 2022 9 e2204513 PMC9762280

[108] Zhang C,Wang Y,Zhen Z,Li J,Su J,Wu C. mTORC1 mediates biphasic mechano-response to orchestrate adhesion-dependent cell growth and anoikis resistance Adv Sci 2024 11 e2307206 PMC10853740

[109] Cruz da Silva E,Dontenwill M,Choulier L,Lehmann M. Role of integrins in resistance to therapies targeting growth factor receptors in cancer Cancers 2019 11 692 PMC6562376

[110] Gao Y,Wei G,Yu H.et al. Integrin β6/Annexin A2 axis triggers autophagy to orchestrate hepatocellular carcinoma radioresistance Cell Death Differ 2025 32 689 701 PMC11982560

[111] Morosi L,Meroni M,Ubezio P.et al. PEGylated recombinant human hyaluronidase (PEGPH20) pre-treatment improves intra-tumour distribution and efficacy of paclitaxel in preclinical models J Exp Clin Cancer Res 2021 40 286 PMC8434701

[112] Whatcott CJ,Han H,Posner RG,Hostetter G,Von Hoff DD. Targeting the tumor microenvironment in cancer: why hyaluronidase deserves a second look Cancer Discov 2011 1 291 6 PMC3204883

[113] Pavel M,Renna M,Park SJ.et al. Contact inhibition controls cell survival and proliferation via YAP/TAZ-autophagy axis Nat Commun 2018 9 2961 PMC6063886

[114] Que K,Tong Y,Que G.et al. Downregulation of miR-874-3p promotes chemotherapeutic resistance in colorectal cancer via inactivation of the Hippo signaling pathway Oncol Rep 2017 38 3376 86 PMC5783584

[115] Putra VDL,Kilian KA,Knothe Tate ML. Stem cell mechanoadaptation. I. Effect of microtubule stabilization and volume changing stresses on cytoskeletal remodeling APL Bioeng 2025 9 016102 PMC11719676

[116] Iero M,Valenti R,Huber V.et al. Tumour-released exosomes and their implications in cancer immunity Cell Death Differ 2008 15 80 8

[117] Rontogianni S,Iskit S,van Doorn S,Peeper DS,Altelaar M. Combined EGFR and ROCK inhibition in triple-negative breast cancer leads to cell death via impaired autophagic flux Mol Cell Proteomics 2020 19 261 77 PMC7000121

[118] Liang ZX,Liu HS,Wang FW.et al. LncRNA RPPH1 promotes colorectal cancer metastasis by interacting with TUBB3 and by promoting exosomes-mediated macrophage M2 polarization Cell Death Dis 2019 10 829 PMC6828701

[119] Chen YD,Fang YT,Cheng YL.et al. Exophagy of annexin A2 via RAB11, RAB8A and RAB27A in IFN-γ-stimulated lung epithelial cells Sci Rep 2017 7 5676 PMC5516008

[120] Guerra F,Bucci C. Role of the RAB7 protein in tumor progression and cisplatin chemoresistance Cancers 2019 11 1096 PMC6721790

[121] Xu S,Cao B,Xuan G.et al. Function and regulation of Rab GTPases in cancers Cell Biol Toxicol 2024 40 28 PMC11065922

[122] Ranieri R,Ciaglia E,Amodio G.et al. N6-isopentenyladenosine dual targeting of AMPK and Rab7 prenylation inhibits melanoma growth through the impairment of autophagic flux Cell Death Differ 2018 25 353 67 PMC5762849

[123] Ning Y,Zheng M,Zhang Y,Jiao Y,Wang J,Zhang S. RhoA-ROCK2 signaling possesses complex pathophysiological functions in cancer progression and shows promising therapeutic potential Cancer Cell Int 2024 24 339 PMC11475559

[124] de Sousa GR,Vieira GM,das Chagas PF,Pezuk JA,Brassesco MS. Should we keep rocking? Portraits from targeting Rho kinases in cancer Pharmacol Res 2020 160 105093

[125] Yakkala PA,Kamal A. Dual-targeting inhibitors involving tubulin for the treatment of cancer Bioorg Chem 2025 156 108116

[126] Lim S,Woo S,Lee KW,Kim KD. Roles of cytoskeleton in metastasis: from its mechanism to therapeutic strategies Exp Mol Med 2026 58 1 13 PMC12868002

[127] Hu Y,Yan C,Mu L.et al. Fibroblast-derived exosomes contribute to chemoresistance through priming cancer stem cells in colorectal cancer PLoS One 2015 10 e0125625 PMC4418721

[128] Catalano M,O'Driscoll L. Inhibiting extracellular vesicles formation and release: a review of EV inhibitors J Extracell Vesicles 2020 9 1703244 PMC6968539

[129] Ha D,Yang N,Nadithe V. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges Acta Pharm Sin B 2016 6 287 96 PMC4951582

[130] Colombo M,Moita C,van Niel G.et al. Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles J Cell Sci 2013 126 5553 65

[131] Tomas A,Vaughan SO,Burgoyne T.et al. WASH and Tsg101/ALIX-dependent diversion of stress-internalized EGFR from the canonical endocytic pathway Nat Commun 2015 6 7324 PMC4490399

[132] Koumangoye RB,Sakwe AM,Goodwin JS,Patel T,Ochieng J. Detachment of breast tumor cells induces rapid secretion of exosomes which subsequently mediate cellular adhesion and spreading PLoS One 2011 6 e24234 PMC3167827

[133] Nishida-Aoki N,Tominaga N,Takeshita F,Sonoda H,Yoshioka Y,Ochiya T. Disruption of circulating extracellular vesicles as a novel therapeutic strategy against cancer metastasis Mol Ther 2017 25 181 91 PMC5363297

[134] Shamseddine AA,Airola MV,Hannun YA. Roles and regulation of neutral sphingomyelinase-2 in cellular and pathological processes Adv Biol Regul 2015 57 24 41 PMC4684640

[135] Mauthe M,Orhon I,Rocchi C.et al. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion Autophagy 2018 14 1435 55 PMC6103682

[136] Fu Z,Cheng X,Kuang J.et al. CQ sensitizes human pancreatic cancer cells to gemcitabine through the lysosomal apoptotic pathway via reactive oxygen species Mol Oncol 2018 12 529 44 PMC5891043

[137] Park D,Lee Y. Biphasic activity of chloroquine in human colorectal cancer cells Dev Reprod 2014 18 225 31 PMC4415643

[138] Huang T,Song X,Yang Y.et al. Autophagy and hallmarks of cancer Crit Rev Oncog 2018 23 247 67 PMC6447410

[139] Law BYK,Gordillo-Martínez F,Qu YQ.et al. Thalidezine, a novel AMPK activator, eliminates apoptosis-resistant cancer cells through energy-mediated autophagic cell death Oncotarget 2017 8 30077 91 PMC5444727

[140] Rezazadeh D,Norooznezhad AH,Mansouri K.et al. Rapamycin reduces cervical cancer cells viability in hypoxic condition: investigation of the role of autophagy and apoptosis Onco Targets Ther 2020 13 4239 47 PMC7244242

[141] Murrow L,Debnath J. ATG12-ATG3 connects basal autophagy and late endosome function Autophagy 2015 11 961 2 PMC4502820

[142] Leidal AM,Debnath J. LC3-dependent extracellular vesicle loading and secretion (LDELS) Autophagy 2020 16 1162 3 PMC7469500

[143] Surana R,Morgado M,Somasundaram A.et al. Open-label, phase II trial of extracellular regulated kinase inhibition alone and in combination with autophagy inhibition in patients with metastatic pancreatic cancer JCO Precis Oncol 2025 9 e2500332 PMC13379901

[144] Lee SM,Hewish M,Ahmed S.et al. Hydroxychloroquine in combination with platinum doublet chemotherapy as first-line treatment for extensive-stage small cell lung cancer (Study 15): a randomised phase II multicentre trial Eur J Cancer 2025 215 115162

[145] Goenka L,Dubashi B,Kayal S.et al. Targeting autophagy in platinum-sensitive relapsed ovarian cancer: randomized phase II trial of hydroxychloroquine with chemotherapy with biomarker correlation Discov Oncol 2025 16 203 PMC11839959

[146] Wolpin BM,Rubinson DA,Wang X.et al. Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma Oncologist 2014 19 637 8 PMC4041680

[147] Piao S,Ojha R,Rebecca VW.et al. ALDH1A1 and HLTF modulate the activity of lysosomal autophagy inhibitors in cancer cells Autophagy 2017 13 2056 71 PMC5788553

[148] Kalli M,Mpekris F,Charalambous A.et al. Mechanical forces inducing oxaliplatin resistance in pancreatic cancer can be targeted by autophagy inhibition Commun Biol 2024 7 1581 PMC11603328

[149] Thakur PC,Miller-Ocuin JL,Nguyen K.et al. Inhibition of endoplasmic-reticulum-stress-mediated autophagy enhances the effectiveness of chemotherapeutics on pancreatic cancer J Transl Med 2018 16 190 PMC6038181

[150] Yuan Y,Li D,Li H,Wang L,Tian G,Dong Y. YAP overexpression promotes the epithelial-mesenchymal transition and chemoresistance in pancreatic cancer cells Mol Med Rep 2016 13 237 42

[151] D'Souza AI,Grover R,Monzon GA,Santen L,Diez S. Vesicles driven by dynein and kinesin exhibit directional reversals without regulators Nat Commun 2023 14 7532 PMC10662051

[152] Vishnubhotla R,Bharadwaj S,Sun S,Metlushko V,Glover SC. Treatment with Y-27632, a ROCK inhibitor, increases the proinvasive nature of SW620 cells on 3D collagen type 1 matrix Int J Cell Biol 2012 2012 259142 PMC3368365

[153] Gu YY,Yu J,Zhang JF,Wang C. Suppressing the secretion of exosomal miR-19b by gw4869 could regulate oxaliplatin sensitivity in colorectal cancer Neoplasma 2019 66 39 45

[154] Mohammad N,Malvi P,Meena AS.et al. Cholesterol depletion by methyl-β-cyclodextrin augments tamoxifen induced cell death by enhancing its uptake in melanoma Mol Cancer 2014 13 204 PMC4175626

[155] Luga V,Zhang L,Viloria-Petit AM.et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration Cell 2012 151 1542 56

[156] Brown SR,Radcliffe ME,Danner JT.et al. Extracellular vesicle-mediated modulation of stem-like phenotype in breast cancer cells under fluid shear stress Biomolecules 2024 14 757 PMC11274421

[157] Arora R,Cao C,Kumar M.et al. Spatial transcriptomics reveals distinct and conserved tumor core and edge architectures that predict survival and targeted therapy response Nat Commun 2023 14 5029 PMC10439131