Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Adipocytes as Orchestrators of Multimodal Cancer Therapy Resistance

  • Jinseon Park (College of Pharmacy, Chung-Ang University) ;
  • Jaebeom Cho (College of Pharmacy, Chung-Ang University)
  • Received : 2026.02.06
  • Accepted : 2026.03.26
  • Published : 2026.05.01
Download PDF
⟨ Previous Next ⟩

Abstract

The emergence of therapy resistance remains a formidable barrier to successful clinical outcomes in oncology, necessitating a deeper understanding of the tumor microenvironment (TME) as a dynamic ecosystem. Adipocytes, once viewed as passive energy reservoirs, are now recognized as active orchestrators of tumor progression and multimodal therapy resistance, particularly in adipose-rich malignancies. This review comprehensively delineates the multifaceted mechanisms through which adipocytes shield cancer cells from therapeutic insults, including chemotherapy, targeted agents, and immunotherapies. We analyze the clinical evidence positioning visceral adiposity as a critical determinant of treatment failure and explore the complex molecular interplay driven by the adipocyte-derived secretome, lipid metabolite-mediated metabolic rewiring, and the horizontal transfer of bioactive cargo via adipocyte-derived extracellular vesicles, and adipocyte-mediated remodeling of the TME. Furthermore, we highlight noncanonical roles such as direct organelle donation, lipid-mediated drug sequestration, the enhancement of DNA repair pathways, and the activation of cell adhesion-dependent survival signaling. We also synthesize recent technological advancements employed to interrogate the intricate adipocyte-cancer interaction. Finally, we discuss emerging therapeutic strategies aimed at disrupting the adipocyte-cancer axis, while critically addressing the translational limitations of these interventions in clinical settings, offering a roadmap for integrating metabolic and anti-inflammatory interventions with standard regimens to overcome adipocyte-driven resistance and advance precision oncology.

Keywords

Acknowledgement

This work was supported by the Chung-Ang University Graduate Research Scholarship in 2025 and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MIST) (RS-2025-24535434). All figures were created with bioRender.com.

References

  1. Ahmad, A., Lee, J., Hong, B. S., Ryu, H. S., Lee, H.-B., Lee, M., Park, I. A., Kim, J., Han, W., Noh, D.-Y. and Moon, H.-G. (2017) Tran sition into inflammatory cancer-associated adipocytes in breast cancer microenvironment requires microRNA regulatory mecha nism. PLos One 12, e0174126.
  2. Becker, A., Thakur, B. K., Weiss, J. M., Kim, H. S., Peinado, H. and Lyden, D. (2016) Extracellular vesicles in cancer: cell-to-cell me diators of metastasis. Cancer Cell. 30, 836-848. https://doi.org/10.1016/j.ccell.2016.10.009
  3. Bejarano, L., Jordāo, M. J. C. and Joyce, J. A. (2021) Therapeutic targeting of the tumor microenvironment. Cancer Discov. 11, 933-959. https://doi.org/10.1158/2159-8290.CD-20-1808
  4. Bessot, A., Gunter, J., McGovern, J. and Bock, N. (2025) Bone mar row adipocytes in cancer: Mechanisms, models, and therapeutic implications. Biomaterials 322, 123341. https://doi.org/10.1016/j.biomaterials.2025.123341
  5. Bluher, M. (2013) Adipose tissue dysfunction contributes to obesity related metabolic diseases. Best Pract. Res. Clin. Endocrinol. Metab. 27, 163-177. https://doi.org/10.1016/j.beem.2013.02.005
  6. Breslin, S. and O'Driscoll, L. (2013) Three-dimensional cell culture: the missing link in drug discovery. Drug Discov. Today 18, 240-249. https://doi.org/10.1016/j.drudis.2012.10.003
  7. Bukowski, K., Kciuk, M. and Kontek, R. (2020) Mechanisms of multi drug resistance in cancer chemotherapy. Int. J. Mol. Sci. 21, 3233.
  8. Cao, Y. (2019) Adipocyte and lipid metabolism in cancer drug resis tance. J. Clin. Invest. 129, 3006-3017. https://doi.org/10.1172/JCI127201
  9. Cao, Z., Liang, N., Yang, H. and Li, S. (2017) Visfatin mediates doxo rubicin resistance in human non-small-cell lung cancer via Akt-me diated up-regulation of ABCC1. Cell Prolif. 50, e12366.
  10. Chaudhary, N., Choudhary, B. S., Shah, S. G., Khapare, N., Dwivedi, N., Gaikwad, A., Joshi, N., Raichanna, J., Basu, S. and Gurjar, M. (2021) Lipocalin 2 expression promotes tumor progression and therapy resistance by inhibiting ferroptosis in colorectal cancer. Int. J. Cancer 149, 1495-1511. https://doi.org/10.1002/ijc.v149.7
  11. Chen, Y.-C., Chien, C.-Y., Hsu, C.-C., Lee, C.-H., Chou, Y.-T., Shiah, S.-G., Liu, S.-Y., Yen, C.-Y., Hsieh, A. C.-T. and Wabitsch, M. (2021) Obesity-associated leptin promotes chemoresistance in colorectal cancer through YAP-dependent AXL upregulation. Am. J. Cancer Res. 11, 4220.
  12. Correa, L. H., Correa, R., Farinasso, C. M., de Sant'Ana Dourado, L. P. and Magalhaes, K. G. (2017) Adipocytes and macrophages inter play in the orchestration of tumor microenvironment: new implica tions in cancer progression. Front. Immunol. 8, 1129.
  13. Dalangood, S., Hu, C., Yuan, C., Li, X., Qiao, W., Li, H., Zhang, R., Li, L., Li, P., Yu, X., Yin, W., Lu, J. and Gui, J. (2025) Cancer-associ ated adipocytes mediate CD8+T cell dysfunction via FGF21-driven lipolysis. Cell Rep. 44, 116526. https://doi.org/10.1016/j.celrep.2025.116526
  14. Del Vecchio, V., Rehman, A., Panda, S. K., Torsiello, M., Marigliano, M., Nicoletti, M. M., Ferraro, G. A., De Falco, V., Lappano, R., Lieto, E., Pagliuca, F., Caputo, C., La Noce, M., Papaccio, G., Tirino, V., Robinson, N., Desiderio, V. and Papaccio, F. (2024) Mitochondrial transfer from Adipose stem cells to breast cancer cells drives multi drug resistance. J. Exp. Clin. Cancer Res. 43, 166.
  15. Dieudonne, M. N., Bussiere, M., Dos Santos, E., Leneveu, M. C., Giu dicelli, Y. and Pecquery, R. (2006) Adiponectin mediates antiproliferative and apoptotic responses in human MCF7 breast cancer cells. Biochem. Biophys. Res. Commun. 345, 271-279. https://doi.org/10.1016/j.bbrc.2006.04.076
  16. Edmondson, R., Broglie, J. J., Adcock, A. F. and Yang, L. (2014) Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay Drug Dev. Tech nol. 12, 207-218.
  17. El Alaa, R. S. A., Al-Mannai, W., Darwish, N. and Al-Mansoori, L. (2024) Adipose-derived stromal cells and cancer-associated fibro blasts: interactions and implications in tumor progression. Int. J. Mol. Sci. 25, 11558.
  18. Emont, M. P., Jacobs, C., Essene, A. L., Pant, D., Tenen, D., Colle luori, G., Di Vincenzo, A., Jorgensen, A. M., Dashti, H., Stefek, A., McGonagle, E., Strobel, S., Laber, S., Agrawal, S., Westcott, G. P., Kar, A., Veregge, M. L., Gulko, A., Srinivasan, H., Kramer, Z., De Filippis, E., Merkel, E., Ducie, J., Boyd, C. G., Gourash, W., Cour coulas, A., Lin, S. J., Lee, B. T., Morris, D., Tobias, A., Khera, A. V., Claussnitzer, M., Pers, T. H., Giordano, A., Ashenberg, O., Regev, A., Tsai, L. T. and Rosen, E. D. (2022) A single-cell atlas of human and mouse white adipose tissue. Nature 603, 926-933. https://doi.org/10.1038/s41586-022-04518-2
  19. Gao, S., Ding, S. and Tang, Z. (2024) A preliminary mechanistic ex ploration of the effect of leptin on the docetaxel sensitivity of MDA-MB-231 triple-negative breast cancer cells. Mol. Clin. Oncol. 20, 24.
  20. Guo, Q., Jin, Y., Chen, X., Ye, X., Shen, X., Lin, M., Zeng, C., Zhou, T. and Zhang, J. (2024) NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduct. Target. Ther. 9, 53.
  21. Gyamfi, J., Lee, Y. H., Eom, M. and Choi, J. (2018) Interleukin-6/STAT3 signalling regulates adipocyte induced epithelial-mesenchymal transition in breast cancer cells. Sci. Rep. 8, 8859.
  22. Han, G., Wang, L., Zhao, W., Yue, Z., Zhao, R., Li, Y., Zhou, X., Hu, X. and Liu, J. (2013) High expression of leptin receptor leads to temo zolomide resistance with exhibiting stem/progenitor cell features in gliobalastoma. Cell Cycle 12, 3833-3840. https://doi.org/10.4161/cc.26809
  23. Hosni, S., Kilian, V., Klumper, N., Gabbia, D., Sieckmann, K., Corvino, D., Winkler, A., Saponaro, M., Worsdorfer, K., Schmidt, D., Hahn, O., Zanotto, I., Bertlich, M., Toma, M., Bald, T., Eckstein, M., Holzel, M., Geyer, M., Ritter, M., Wachten, D., De Martin, S. and Alajati, A. (2024) Adipocyte precursor-derived NRG1 promotes resistance to FGFR inhibition in urothelial carcinoma. Cancer Res. 84, 725-740. https://doi.org/10.1158/0008-5472.CAN-23-1398
  24. Huang, W. S., Wu, K. L., Chen, C. N., Chang, S. F., Lee, D. Y. and Lee, K. C. (2024) Amphiregulin upregulation in visfatin-stimulated colorectal cancer cells reduces sensitivity to 5-fluororacil cytotoxic ity. Biology (Basel) 13, 821.
  25. Ibrahim, M. M. (2010) Subcutaneous and visceral adipose tissue: structural and functional differences. Obes. Rev. 11, 11-18. https://doi.org/10.1111/obr.2010.11.issue-1
  26. Incio, J., Ligibel, J. A., McManus, D. T., Suboj, P., Jung, K., Kawaguchi, K., Pinter, M., Babykutty, S., Chin, S. M., Vardam, T. D., Huang, Y., Rahbari, N. N., Roberge, S., Wang, D., Gomes-Santos, I. L., Puch ner, S. B., Schlett, C. L., Hoffmman, U., Ancukiewicz, M., Tolaney, S. M., Krop, I. E., Duda, D. G., Boucher, Y., Fukumura, D. and Jain, R. K. (2018) Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2. Sci. Transl. Med. 10, eaag0945. https://doi.org/10.1126/scitranslmed.aag0945
  27. Ju, Y., Liu, X., Na, J., He, J., Wu, L., Wang, Z., Peng, C., Liao, Y. and Zhang, Z. (2025) LncRNA TMPO-AS1 facilitates cervical cancer cell tumorigenesis and ferroptosis resistance via interaction with LCN2. Sci. Rep. 15, 22604.
  28. Keesling, A. R., Rondini, E. A. and Granneman, J. G. (2025) Spatial transcriptomics of adipose tissue: technologies, applications, and challenges. J. Obes. Metab. Syndr. 34, 362-377. https://doi.org/10.7570/jomes25078
  29. Kershaw, E. E. and Flier, J. S. (2004) Adipose tissue as an endocrine organ. J. Clin. Endocrinol. Metab. 89, 2548-2556. https://doi.org/10.1210/jc.2004-0395
  30. Kwak, J. G. and Lee, J. (2023) Bone marrow adipocytes contribute to tumor microenvironment-driven chemoresistance via sequestration of doxorubicin. Cancers (Basel) 15, 2737. https://doi.org/10.3390/cancers15102737
  31. La Camera, G., Gelsomino, L., Malivindi, R., Barone, I., Panza, S., De Rose, D., Giordano, F., D'Esposito, V., Formisano, P., Bonofiglio, D., Ando, S., Giordano, C. and Catalano, S. (2021) Adipocyte-de rived extracellular vesicles promote breast cancer cell malignancy through HIF-1alpha activity. Cancer Lett. 521, 155-168. https://doi.org/10.1016/j.canlet.2021.08.021
  32. Lazar, I., Clement, E., Dauvillier, S., Milhas, D., Ducoux-Petit, M. LeGonidec, S., Moro, C., Soldan, V., Dalle, S., Balor, S., Golzio, M., Burlet-Schiltz, O., Valet, P., Muller, C. and Nieto, L. (2016) Adipocyte exosomes promote melanoma aggressiveness through fatty acid oxidation: a novel mechanism linking obesity and can cer. Cancer Res. 76, 4051-4057. https://doi.org/10.1158/0008-5472.CAN-16-0651
  33. Lee, C. S., Murphy, D. J., McMahon, C., Nolan, B., Cullen, G., Mulcahy, H., Sheahan, K., Barnes, E., Fennelly, D., Ryan, E. J. and Doherty, G. A. (2015) Visceral adiposity is a risk factor for poor prognosis in colorectal cancer patients receiving adjuvant chemotherapy. J. Gastrointest. Cancer 46, 243-250. https://doi.org/10.1007/s12029-015-9709-0
  34. Lee, K. C., Wu, K. L., Yen, C. K., Chang, S. F., Chen, C. N. and Lu, Y. C. (2022) Inhibition of NLRP3 by fermented quercetin decreas es resistin-induced chemoresistance to 5-fluorouracil in human colorectal cancer cells. Pharmaceuticals (Basel) 15, 798. https://doi.org/10.3390/ph15070798
  35. Lee, M. J., Wu, Y. and Fried, S. K. (2013) Adipose tissue heterogene ity: implication of depot differences in adipose tissue for obesity complications. Mol. Aspects Med. 34, 1-11. https://doi.org/10.1016/j.mam.2012.10.001
  36. Lei, M., Li, J., Ren, X., Xie, H., Li, P., Qi, F., Shi, J., Cai, X., Liu, Y., Chen, P., Feng, X., Xia, L., Wang, F., Li, H., Guo, M., Zhang, Y., Liu, B. F. and Li, Y. (2025) Tumor-adipose assembloids reveal cell fate-transition-triggered multistage collective invasions. Cell Syst. 16, 101353. https://doi.org/10.1016/j.cels.2025.101353
  37. Li, Z., Zhang, C., Du, J. X., Zhao, J., Shi, M. T., Jin, M. W. and Liu, H. (2020) Adipocytes promote tumor progression and induce PD-L1 expression via TNF-alpha/IL-6 signaling. Cancer Cell Int. 20, 179. https://doi.org/10.1186/s12935-020-01269-w
  38. Liang, Y., Li, Z., Tang, L., Pan, Z., Fei, X., Tan, C., He, A., Yang, Q. and Cheng, D. (2025) Adipocytes promote cisplatin resistance through secreting A1BG and regulating NAMPT/PARP1 axis-mediated DNA repair in osteosarcoma. Adv. Sci. (Weinh.) 12, e02926. https://doi.org/10.1002/advs.v12.35
  39. Lin, C. N., Liang, Y. L., Tsai, H. F., Wu, P. Y., Huang, L. Y., Lin, Y. H., Kang, C. Y., Yao, C. L., Shen, M. R. and Hsu, K. F. (2024) Adi pocyte pyroptosis occurs in omental tumor microenvironment and is associated with chemoresistance of ovarian cancer. J. Biomed. Sci. 31, 62.
  40. Liotti, A., La Civita, E., Cennamo, M., Crocetto, F., Ferro, M., Guadag no, E., Insabato, L., Imbimbo, C., Palmieri, A., Mirone, V., Liguoro, P., Formisano, P., Beguinot, F. and Terracciano, D. (2021) Peri prostatic adipose tissue promotes prostate cancer resistance to docetaxel by paracrine IGF-1 upregulation of TUBB2B beta-tubulin isoform. Prostate 81, 407-417. https://doi.org/10.1002/pros.v81.7
  41. Litton, J. K., Gonzalez-Angulo, A. M., Warneke, C. L., Buzdar, A. U., Kau, S.-W., Bondy, M., Mahabir, S., Hortobagyi, G. N. and Brew ster, A. M. (2008) Relationship between obesity and pathologic response to neoadjuvant chemotherapy among women with oper able breast cancer. J. Clin. Oncol. 26, 4072-4077. https://doi.org/10.1200/JCO.2007.14.4527
  42. Liu, S., Benito-Martin, A., Pelissier Vatter, F. A., Hanif, S. Z., Liu, C., Bhardwaj, P., Sethupathy, P., Farghli, A. R., Piloco, P., Paik, P., Mushannen, M., Dong, X., Otterburn, D. M., Cohen, L., Bareja, R., Krumsiek, J., Cohen-Gould, L., Calto, S., Spector, J. A., Elemento, O., Lyden, D. C. and Brown, K. A. (2023) Breast adipose tissue derived extracellular vesicles from obese women alter tumor cell metabolism. EMBO Rep. 24, e57339. https://doi.org/10.15252/embr.202357339
  43. Liu, Z., Shi, A., Song, D., Han, B., Zhang, Z., Ma, L., Liu, D. and Fan, Z. (2017) Resistin confers resistance to doxorubicin-induced apopto sis in human breast cancer cells through autophagy induction. Am. J. Cancer Res. 7, 574.
  44. Lv, X., Li, Z., Dai, Y., Xiao, Y., Shen, F., Wang, J., Cao, J., Wang, L., Peng, Q. and Jiao, Y. (2024) The mir-199b-5p encapsulated in ad ipocyte-derived exosomes mediates radioresistance of colorectal cancer cells by targeting JAG1. Heliyon 10, e24412.
  45. Ma, L., Fan, Z., Du, G. and Wang, H. (2019) Leptin-elicited miRNA 342-3p potentiates gemcitabine resistance in pancreatic ductal ad enocarcinoma. Biochem. Biophys. Res. Commun. 509, 845-853. https://doi.org/10.1016/j.bbrc.2019.01.030
  46. Ma, X., Xiao, L., Liu, L., Ye, L., Su, P., Bi, E., Wang, Q., Yang, M., Qian, J. and Yi, Q. (2021) CD36-mediated ferroptosis dampens in tratumoral CD8+ T cell effector function and impairs their antitumor ability. Cell Metab. 33, 1001-1012.e5. https://doi.org/10.1016/j.cmet.2021.02.015
  47. Malvi, P., Chaube, B., Singh, S. V., Mohammad, N., Vijayakumar, M. V., Singh, S., Chouhan, S. and Bhat, M. K. (2018) Elevated cir culatory levels of leptin and resistin impair therapeutic efficacy of dacarbazine in melanoma under obese state. Cancer Metab. 6, 2. https://doi.org/10.1186/s40170-018-0176-5
  48. Mandl, M., Viertler, H. P., Hatzmann, F. M., Brucker, C., Grossmann, S., Waldegger, P., Rauchenwald, T., Mattesich, M., Zwierzina, M., Pierer, G. and Zwerschke, W. (2022) An organoid model derived from human adipose stem/progenitor cells to study adipose tissue physiology. Adipocyte 11, 164-174. https://doi.org/10.1080/21623945.2022.2044601
  49. Massier, L., Jalkanen, J., Elmastas, M., Zhong, J., Wang, T., Nono Nankam, P. A., Frendo-Cumbo, S., Backdahl, J., Subramanian, N., Sekine, T., Kerr, A. G., Tseng, B. T. P., Laurencikiene, J., Buggert, M., Lourda, M., Kublickiene, K., Bhalla, N., Andersson, A., Vals esia, A., Astrup, A., Blaak, E. E., Stahl, P. L., Viguerie, N., Lan gin, D., Wolfrum, C., Bluher, M., Ryden, M. and Mejhert, N. (2023) An integrated single cell and spatial transcriptomic map of human white adipose tissue. Nat. Commun. 14, 1438.
  50. Mentoor, I., Engelbrecht, A. M., van de Vyver, M., van Jaarsveld, P. J. and Nell, T. (2021) The paracrine effects of adipocytes on lipid metabolism in doxorubicin-treated triple negative breast cancer cells. Adipocyte 10, 505-523. https://doi.org/10.1080/21623945.2021.1979758
  51. Mertz, D. R., Parigoris, E., Sentosa, J., Lee, J. H., Lee, S., Kleer, C. G., Luker, G. and Takayama, S. (2023) Triple-negative breast cancer cells invade adipocyte/preadipocyte-encapsulating geometrically inverted mammary organoids. Integr. Biol. (Camb.) 15, zyad004.  https://doi.org/10.1093/intbio/zyad004
  52. Morteza, G. and Amirhossein, S. (2016) Interleukin-6: a critical cyto kine in cancer multidrug resistance. Curr. Pharm. Des. 22, 518-526. https://doi.org/10.2174/1381612822666151124234417
  53. Naimo, G. D., Forestiero, M., Giordano, F., Leonetti, A. E., Gelsomino, L., Panno, M. L., Ando, S. and Mauro, L. (2025) Adiponectin influ ences the behavior of stem cells in hormone-resistant breast can cer. Cells. 14, 286. https://doi.org/10.3390/cells14040286
  54. Navas, L. E. and Carnero, A. (2021) NAD(+) metabolism, stemness, the immune response, and cancer. Signal Transduct. Target. Ther. 6, 2.
  55. Norreen-Thorsen, M., Struck, E. C., Oling, S., Zwahlen, M., Von Feilit zen, K., Odeberg, J., Lindskog, C., Ponten, F., Uhlen, M., Dusart, P. J. and Butler, L. M. (2022) A human adipose tissue cell-type tran scriptome atlas. Cell Rep. 40, 111046. https://doi.org/10.1016/j.celrep.2022.111046
  56. O'Connell, F., Mylod, E., Donlon, N. E., Davern, M., Butler, C., O'Connor, N., Menon, M. S., Donohoe, C. L., Ravi, N., Doherty, D. G., Dunne, M. R., Reynolds, J. V., Roche, H. M. and O'Sullivan, J. (2025) Adipose tissue from oesophageal adenocarcinoma patients is differentially affected by chemotherapy and chemoradiotherapy regimens altering immune cell phenotype and cancer cell metabo lism. Transl. Oncol. 53, 102302. https://doi.org/10.1016/j.tranon.2025.102302
  57. Ochiai, M., Fierstein, S., XsSali, F., DeVito, N., Purkey, L. R., May, R., Correa-Medina, A., Kelley, M., Page, T. D. and DeCicco-Skinner, K. (2023) Unlocking drug resistance in multiple myeloma: adipocytes as modulators of treatment response. Cancers (Basel) 15, 4347. https://doi.org/10.3390/cancers15174347
  58. Ouchi, N., Parker, J. L., Lugus, J. J. and Walsh, K. (2011) Adipokines in inflammation and metabolic disease. Nat. Rev. Immunol. 11, 85-97. https://doi.org/10.1038/nri2921
  59. Pang, J., Shi, Q., Liu, Z., He, J., Liu, H., Lin, P., Cui, J. and Yang, J. (2017) Resistin induces multidrug resistance in myeloma by inhibit ing cell death and upregulating ABC transporter expression. Hae matologica 102, 1273-1280. https://doi.org/10.3324/haematol.2016.154062
  60. Petrelli, F., Cortellini, A., Indini, A., Tomasello, G., Ghidini, M., Nigro, O., Salati, M., Dottorini, L., Iaculli, A., Varricchio, A., Rampulla, V., Barni, S., Cabiddu, M., Bossi, A., Ghidini, A. and Zaniboni, A. (2021) Association of obesity with survival outcomes in patients with cancer: a systematic review and meta-analysis. JAMA Netw. Open 4, e213520. https://doi.org/10.1001/jamanetworkopen.2021.3520
  61. Piwocka, O., Piotrowski, I., Suchorska, W. M. and Kulcenty, K. (2024) Dynamic interactions in the tumor niche: how the cross-talk be tween CAFs and the tumor microenvironment impacts resistance to therapy. Front. Mol. Biosci. 11, 1343523. https://doi.org/10.3389/fmolb.2024.1343523
  62. Quan, Y., Li, J., Cai, J., Liao, Y., Zhang, Y. and Lu, F. (2024) Trans plantation of beige adipose organoids fabricated using adipose acellular matrix hydrogel improves metabolic dysfunction in high fat diet-induced obesity and type 2 diabetes mice. J. Cell. Physiol. 239, e31191.
  63. Ruan, G. T., Zhu, L. C., Xie, H. L., Zhang, H. Y., Song, M. M., Deng, L. and Shi, H. P. (2025) Adipocyte-derived IL6 and triple-negative breast cancer cell-derived CXCL1 co-activate STAT3/NF-kappaB pathway to mediate the crosstalk between adipocytes and triple negative breast cancer cells. Cell Death Discov. 11, 395. https://doi.org/10.1038/s41420-025-02713-4
  64. Sato, S., Hiruma, T., Koizumi, M., Yoshihara, M., Nakamura, Y., Tado koro, H., Motomatsu, S., Yamanaka, T., Washimi, K., Okubo, Y., Yoshioka, E., Kasajima, R., Yamashita, T., Kishida, T., Yokose, T. and Miyagi, Y. (2023) Bone marrow adipocytes induce cancer-as sociated fibroblasts and immune evasion, enhancing invasion and drug resistance. Cancer Sci. 114, 2674-2688. https://doi.org/10.1111/cas.v114.6
  65. Schoettl, T., Fischer, I. P. and Ussar, S. (2018) Heterogeneity of adi pose tissue in development and metabolic function. J. Exp. Biol. 221, jeb162958.
  66. Shi, C., Wang, C., Fu, Z., Liu, J., Zhou, Y., Cheng, B., Zhang, C., Li, S. and Zhang, Y. (2024) Lipocalin 2 (LCN2) confers acquired resis tance to almonertinib in NSCLC through LCN2-MMP-9 signaling pathway. Pharmacol. Res. 201, 107088.
  67. Steppan, C. M., Bailey, S. T., Bhat, S., Brown, E. J., Banerjee, R. R., Wright, C. M., Patel, H. R., Ahima, R. S. and Lazar, M. A. (2001) The hormone resistin links obesity to diabetes. Nature 409, 307-312. https://doi.org/10.1038/35053000
  68. Strobel, H. A., Gerton, T. and Hoying, J. B. (2021) Vascularized adi pocyte organoid model using isolated human microvessel frag ments. Biofabrication 13, 035022. https://doi.org/10.1088/1758-5090/abe187
  69. Strusi, G., Suelzu, C. M. and Stebbing, J. (2026) Modelling adipose tissue-cancer crosstalk: a three-dimensional perspective. Onco gene 45, 905-913. https://doi.org/10.1038/s41388-026-03697-w
  70. Su, Y.-H., Wu, Y.-Z., Ann, D. K., Chen, J. L.-Y. and Kuo, C.-Y. (2023) Obesity promotes radioresistance through SERPINE1-mediated aggressiveness and DNA repair of triple-negative breast can cer. Cell Death Dis. 14, 53. https://doi.org/10.1038/s41419-023-05576-8
  71. Sun, C., Li, X., Guo, E., Li, N., Zhou, B., Lu, H., Huang, J., Xia, M., Shan, W., Wang, B., Li, K., Weng, D., Xu, X., Gao, Q., Wang, S., Hu, J., Lu, Y., Mills, G. B. and Chen, G. (2020) MCP-1/CCR-2 axis in adipocytes and cancer cell respectively facilitates ovarian cancer peritoneal metastasis. Oncogene 39, 1681-1695. https://doi.org/10.1038/s41388-019-1090-1
  72. Sun, P., Liu, F., Huo, K., Wang, J., Cheng, Y., Shang, S., Ma, W., Yu, J. and Han, J. (2025) Adiponectin facilitates the cell cycle, inhibits cell apoptosis and induces temozolomide resistance in glioblastoma via the Akt/mTOR pathway. Oncol. Lett. 29, 127.
  73. Tabe, Y., Saitoh, K., Yang, H., Sekihara, K., Yamatani, K., Ruvolo, V., Taka, H., Kaga, N., Kikkawa, M., Arai, H., Miida, T., Andreeff, M., Spagnuolo, P. A. and Konopleva, M. (2018) Inhibition of FAO in AML co-cultured with BM adipocytes: mechanisms of survival and chemosensitization to cytarabine. Sci. Rep. 8, 16837. https://doi.org/10.1038/s41598-018-35198-6
  74. Tabe, Y., Yamamoto, S., Saitoh, K., Sekihara, K., Monma, N., Ikeo, K., Mogushi, K., Shikami, M., Ruvolo, V., Ishizawa, J., Hail, N., Jr., Kazuno, S., Igarashi, M., Matsushita, H., Yamanaka, Y., Arai, H., Nagaoka, I., Miida, T., Hayashizaki, Y., Konopleva, M. and Andreeff, M. (2017) Bone marrow adipocytes facilitate fatty acid oxidation ac tivating AMPK and a transcriptional network supporting survival of acute monocytic leukemia cells. Cancer Res. 77, 1453-1464. https://doi.org/10.1158/0008-5472.CAN-16-1645
  75. Takabe, K., Chen, S., Chen, C.-M., Zhou, Y., Zhou, R.-J., Yu, K.-D. and Shao, Z.-M. (2012) Obesity or overweight is associated with worse pathological response to neoadjuvant chemotherapy among Chinese women with breast cancer. PLoS One 7, e41380.
  76. Tchkonia, T., Thomou, T., Zhu, Y., Karagiannides, I., Pothoulakis, C., Jensen, M. D. and Kirkland, J. L. (2013) Mechanisms and meta bolic implications of regional differences among fat depots. Cell Metab. 17, 644-656. https://doi.org/10.1016/j.cmet.2013.03.008
  77. Tucci, J., Chen, T., Margulis, K., Orgel, E., Paszkiewicz, R. L., Cohen, M. D., Oberley, M. J., Wahhab, R., Jones, A. E., Divakaruni, A. S., Hsu, C. C., Noll, S. E., Sheng, X., Zare, R. N. and Mittelman, S. D. (2021) Adipocytes provide fatty acids to acute lymphoblastic leuke mia cells. Front. Oncol. 11, 665763.
  78. VanSaun, M. N. (2013) Molecular pathways: adiponectin and leptin signaling in cancer. Clin. Cancer Res. 19, 1926-1932. https://doi.org/10.1158/1078-0432.CCR-12-0930
  79. Vasan, N., Baselga, J. and Hyman, D. M. (2019) A view on drug resis tance in cancer. Nature 575, 299-309. https://doi.org/10.1038/s41586-019-1730-1
  80. Vijay, J., Gauthier, M. F., Biswell, R. L., Louiselle, D. A., Johnston, J. J., Cheung, W. A., Belden, B., Pramatarova, A., Biertho, L., Gibson, M., Simon, M. M., Djambazian, H., Staffa, A., Bourque, G., Laitinen, A., Nystedt, J., Vohl, M. C., Fraser, J. D., Pastinen, T., Tchernof, A. and Grundberg, E. (2020) Single-cell analysis of human adipose tissue identifies depot and disease specific cell types. Nat. Metab. 2, 97-109.
  81. Wang, H., Zhang, S., Yee, D., Basu, S., Beckwith, H., Potter, D. and Blaes, A. (2021a) Impact of body mass index on pathological com plete response following neoadjuvant chemotherapy in operable breast cancer: a meta-analysis. Breast Cancer 28, 618-629. https://doi.org/10.1007/s12282-020-01194-w
  82. Wang, T., Fahrmann, J. F., Lee, H., Li, Y. J., Tripathi, S. C., Yue, C., Zhang, C., Lifshitz, V., Song, J., Yuan, Y., Somlo, G., Jandial, R., Ann, D., Hanash, S., Jove, R. and Yu, H. (2018) JAK/STAT3-regu lated fatty acid beta-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab. 27, 136-150.e5. https://doi.org/10.1016/j.cmet.2017.11.001
  83. Wang, T., Sharma, A. K. and Wolfrum, C. (2022a) Novel insights into adipose tissue heterogeneity. Rev. Endocr. Metab. Disord. 23, 5-12. https://doi.org/10.1007/s11154-021-09703-8
  84. Wang, W. J., Lai, H. Y., Zhang, F., Shen, W. J., Chu, P. Y., Liang, H. Y., Liu, Y. B. and Wang, J. M. (2021b) MCL1 participates in leptin promoted mitochondrial fusion and contributes to drug resistance in gallbladder cancer. JCI Insight 6, e135438. https://doi.org/10.1172/jci.insight.135438
  85. Wang, X. and Lin, Y. (2008) Tumor necrosis factor and cancer, buddies or foes? Acta Pharmacol. Sin. 29, 1275-1288. https://doi.org/10.1111/j.1745-7254.2008.00889.x
  86. Wang, Y. Y., Attane, C., Milhas, D., Dirat, B., Dauvillier, S., Guerard, A., Gilhodes, J., Lazar, I., Alet, N., Laurent, V., Le Gonidec, S., Biard, D., Herve, C., Bost, F., Ren, G. S., Bono, F., Escourrou, G., Prentki, M., Nieto, L., Valet, P. and Muller, C. (2017) Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. JCI Insight 2, e87489. https://doi.org/10.1172/jci.insight.87489
  87. Wang, Z., He, J., Bach, D. H., Huang, Y. H., Li, Z., Liu, H., Lin, P. and Yang, J. (2022b) Induction of m(6)A methylation in adipocyte exo somal LncRNAs mediates myeloma drug resistance. J. Exp. Clin. Cancer Res. 41, 4. https://doi.org/10.1186/s13046-021-02209-w
  88. Wen, Y. A., Xing, X., Harris, J. W., Zaytseva, Y. Y., Mitov, M. I., Napier, D. L., Weiss, H. L., Mark Evers, B. and Gao, T. (2017) Adipocytes activate mitochondrial fatty acid oxidation and autophagy to pro mote tumor growth in colon cancer. Cell Death Dis. 8, e2593.
  89. Williams, M. E., Howard, D., Donnelly, C., Izadi, F., Parra, J. G., Pugh, M., Edwards, K., Lutchman-Sigh, K., Jones, S., Margarit, L., Fran cis, L., Conlan, R. S., Taraballi, F. and Gonzalez, D. (2024) Adipo cyte derived exosomes promote cell invasion and challenge pa clitaxel efficacy in ovarian cancer. Cell Commun. Signal. 22, 443.
  90. Wu, Q., Li, B., Li, Z., Li, J., Sun, S. and Sun, S. (2019) Cancer-as sociated adipocytes: key players in breast cancer progression. J. Hematol. Oncol. 12, 95.
  91. Yan, X., Zhao, J. and Zhang, R. (2017) Visfatin mediates doxorubicin resistance in human colorectal cancer cells via up regulation of multidrug resistance 1 (MDR1). Cancer Chemother. Pharmacol. 80, 395-403. https://doi.org/10.1007/s00280-017-3365-y
  92. Yang, J., Zaman, M. M., Vlasakov, I., Roy, R., Huang, L., Martin, C. R., Freedman, S. D., Serhan, C. N. and Moses, M. A. (2019) Adi pocytes promote ovarian cancer chemoresistance. Sci. Rep. 9, 13316.
  93. Yao, H. and He, S. (2021) Multi-faceted role of cancer-associated adi pocytes in the tumor microenvironment (Review). Mol. Med. Rep. 24, 866.
  94. Yoshida, H. and Fujiwara, K. (2023) Adipose tissue area is a predic tive biomarker for the efficacy of pegylated liposomal doxorubicin in platinum-refractory/resistant ovarian cancer. Cancer Med. 12, 14196-14206. https://doi.org/10.1002/cam4.v12.13
  95. Zhang, A. M. Y., Wellberg, E. A., Kopp, J. L. and Johnson, J. D. (2021) Hyperinsulinemia in obesity, inflammation, and cancer. Diabetes Metab. J. 45, 285-311. https://doi.org/10.4093/dmj.2020.0250
  96. Zhang, Q., Deng, T., Zhang, H., Zuo, D., Zhu, Q., Bai, M., Liu, R., Ning, T., Zhang, L., Yu, Z., Zhang, H. and Ba, Y. (2022) Adipocyte-derived exosomal MTTP suppresses ferroptosis and promotes chemore sistance in colorectal cancer. Adv. Sci. (Weinh.) 9, e2203357.
  97. Zhao, H., Wu, L., Yan, G., Chen, Y., Zhou, M., Wu, Y. and Li, Y. (2021) Inflammation and tumor progression: signaling pathways and tar geted intervention. Signal Transduct. Target. Ther. 6, 263.
  98. Zhao, Q., Long, Y., Cheng, W., Huang, Y., Li, J., Li, Y., Li, X., Guo, X., Li, Y., Li, G., Gong, K. and Zhang, J. (2022) Visfatin inhibits colon cancer cell apoptosis and decreases chemosensitivity to 5-FU by promoting the SDF-1/CXCR4/Akt axis. Int. J. Oncol. 60, 1-13. https://doi.org/10.3892/ijo
  99. Zhou, C., Huang, Y. Q., Da, M. X., Jin, W. L. and Zhou, F. H. (2023) Adipocyte-derived extracellular vesicles: bridging the communica tions between obesity and tumor microenvironment. Discov. Oncol. 14, 92.