Comprehensive multi-omics analysis of CD36 in pan-cancers: Evaluating role in prognosis, immune microenvironment, and therapeutic response

Abstract

Cluster of differentiation-36 (CD36) is involved in cellular adhesion, lipid metabolism, immunity, and inflammation. Multiple studies have enlightened the regulatory roles of CD36 in metabolic reprogramming, metastasis, chemoresistance, stemness, immune modulation, senescence, inflammation, and angiogenesis. However, its role in tumorigenesis is still unclear and context-dependent. We performed a comprehensive pan-cancer analysis of CD36 by using data from TCGA, integrating transcriptomic, proteomic, methylation, mutational, immune infiltration, immunotherapy, and drug sensitivity datasets. Expression patterns, clinical associations, prognostic potential, immune interactions, and therapeutic implications were systematically evaluated. We also evaluated CD36-related molecular pathways and immune signatures in cancer by a comprehensive GSEA analysis. We found that CD36 expression pattern is dysregulated in multiple cancer types, whereas higher expression correlated with poor prognosis in LGG, BRCA, CESC, and LAML. CD36 mRNA showed inverse correlations with methylation levels. GSEA analysis revealed cancer-type-dependent association of CD36 with hallmark pathways, whereas multiple cancer types showed positive correlation with immune and inflammation-related pathways and negative correlation with cell cycle-related pathways. CD36 expression correlated with macrophage infiltration, immune regulators, and immunotherapy outcomes, including T-cell dysfunction and Immune checkpoint blockade (ICB) response. Moreover, drug sensitivity analyses revealed significant associations between CD36 and anticancer compound responses. This study provides a comprehensive and context-dependent landscape of CD36, establishing its oncogenic and immune-regulatory roles. Our findings highlight the potential of CD36 in prognosis, tumor microenvironment, and therapeutic sensitivity, while experimental validation is required to prove therapeutic relevance in cancer therapy and immunotherapy.

Keywords

CD36 / Pan-cancer / Immune microenvironment / Prognosis / Immunotherapy / Drug sensitivity

CRediT authorship contribution statement

Muhammad Sameer Ashaq: Writing - review & editing, Methodology, Data curation, Conceptualization. Shengsong Wang: Validation, Data curation. Meiqi Guo: Validation. Lingling Wang: Validation. Zhuoran Li: Validation. Yi Wang: Validation. Yufeng Huang: Validation. Yuan Li: Writing - review & editing, Conceptualization. Baobing Zhao: Writing - review & editing, Supervision, Conceptualization.

Ethics approval

Not applicable.

Declaration of generative AI in scientific writing

Not applicable.

Funding information

This work was supported by grants from the National Key Research and Development Program of China (2024YFC2510500, to B.Z.), National Natural Science Foundation of China (82200989, to Y.L.), Natural Science Foundation of Shandong Province (ZR2024MH065, to Y.L.) and the key Program of Innovation Improvement of Small and Medium-sized Enterprises of Shandong Province in China (2023TSGC0717, to B.Z.).

Data availability

Data will be available on request.

Conflict of interest

The authors declare no competing financial interests and personal relationship that could have appeared to influence the work reported in this manuscript.

Acknowledgments

We thank Translational Medicine Core Facility and Core Facility of school of Basic Medical Sciences of Shandong University for the consultation and instrument availability that supported this work.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.pscia.2025.100097.

References

[1] S.M. Schwartz, Epidemiology of cancer, Clin. Chem. 70 (1) (2024) 140-149, https://doi.org/10.1093/clinchem/hvad202.

[2] R.L. Siegel, A.N. Giaquinto, A. Jemal, Cancer statistics, 2024, CA Cancer J. Clin. 74 (1) (2024) 12-49, https://doi.org/10.3322/caac.21820.

[3] B. Han, R. Zheng, H. Zeng, S. Wang, K. Sun, R. Chen, L. Li, W. Wei, J. He, Cancer incidence and mortality in China, 2022, J. Natl. Cancer. Cent. 4 (1) (2024) 47-53, https://doi.org/10.1016/j.jncc.2024.01.006.

[4] C. Xia, P. Basu, B.S. Kramer, H. Li, C. Qu, X.Q. Yu, K. Canfell, Y. Qiao, B. K. Armstrong, W. Chen, Cancer screening in China: a steep road from evidence to implementation, Lancet Public Health 8 (12) (2023) e996-e1005, https://doi.org/10.1016/S2468-2667(23)00186-X.

[5] J. Boshuizen, D.S. Peeper, Rational cancer treatment combinations: an urgent clinical need, Mol. Cell. 78 (6) (2020) 1002-1018, https://doi.org/10.1016/j.molcel.2020.05.031.

[6] A. Passaro, M. Al Bakir, E.G. Hamilton, M. Diehn, F. André, S. Roy-Chowdhuri, G. Mountzios, I.I. Wistuba, C. Swanton, S. Peters, Cancer biomarkers: emerging trends and clinical implications for personalized treatment, Cell 187 (7) (2024) 1617-1635, https://doi.org/10.1016/j.cell.2024.02.041.

[7] P.A. Ascierto, M. Casula, J. Bulgarelli, M. Pisano, C. Piccinini, L. Piccin, A. Cossu, M. Mandalà, P.F. Ferrucci, M. Guidoboni, P. Rutkowski, V. Ferraresi, A. Arance, M. Guida, E. Maiello, H. Gogas, E. Richtig, M.T. Fierro, C. Lebbe, H. Helgadottir, P. Queirolo, F. Spagnolo, M. Tucci, M. Del Vecchio, M.G. Cao, A.M. Minisini, S. De Placido, M.F. Sanmamed, D. Mallardo, M. Paone, M.G. Vitale, I. Melero, A. M. Grimaldi, D. Giannarelli, R. Dummer, V.C. Sileni, G. Palmieri, Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial, Nat. Commun. 15 (1) (2024) 146, https://doi.org/10.1038/s41467-023-44475-6.

[8] M. Wang, J. Munoz, A. Goy, F.L. Locke, C.A. Jacobson, B.T. Hill, J.M. Timmerman, H. Holmes, S. Jaglowski, I.W. Flinn, P.A. McSweeney, D.B. Miklos, J.M. Pagel, M. J. Kersten, N. Milpied, H. Fung, M.S. Topp, R. Houot, A. Beitinjaneh, W. Peng, L. Zheng, J.M. Rossi, R.K. Jain, A.V. Rao, P.M. Reagan, KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma, N. Engl. J. Med. 382 (14) (2020) 1331-1342, https://doi.org/10.1056/NEJMoa1914347.

[9] Y. Li, Y. Dou, F. Da Veiga Leprevost, Y. Geffen, A.P. Calinawan, F. Aguet, Y. Akiyama, S. Anand, C. Birger, S. Cao, R. Chaudhary, P. Chilappagari, M. Cieslik, A. Colaprico, D.C. Zhou, C. Day, M.J. Domagalski, M. Esai Selvan, D. Fenyö, S. M. Foltz, A. Francis, T. Gonzalez-Robles, Z.H. Gümüş, D. Heiman, M. Holck, R. Hong, Y. Hu, E.J. Jaehnig, J. Ji, W. Jiang, L. Katsnelson, K.A. Ketchum, R. J. Klein, J.T. Lei, W.W. Liang, Y. Liao, C.M. Lindgren, W. Ma, L. Ma, M.J. MacCoss, F. Martins Rodrigues, W. McKerrow, N. Nguyen, R. Oldroyd, A. Pilozzi, P. Pugliese, B. Reva, P. Rudnick, K.V. Ruggles, D. Rykunov, S.R. Savage, M. Schnaubelt, T. Schraink, Z. Shi, D. Singhal, X. Song, E. Storrs, N.V. Terekhanova, R. R. Thangudu, M. Thiagarajan, L.B. Wang, J.M. Wang, Y. Wang, B. Wen, Y. Wu, M. A. Wyczalkowski, Y. Xin, L. Yao, X. Yi, H. Zhang, Q. Zhang, M. Zuhl, G. Getz, L. Ding, A.I. Nesvizhskii, P. Wang, A.I. Robles, B. Zhang, S.H. Payne, Proteogenomic data and resources for pan-cancer analysis, Cancer Cell 41 (8) (2023) 1397-1406, https://doi.org/10.1016/j.ccell.2023.06.009.

[10] N.J. Mullen, P.K. Singh, Nucleotide metabolism: a pan-cancer metabolic dependency, Nat. Rev. Cancer 23 (5) (2023) 275-294, https://doi.org/10.1038/s41568-023-00557-7.

[11] F. Zhong, Y. Zeng, Y. Yan, L. Guo, Q. Guo, W. Liu, C. Liu, Comprehensive multiomics analysis of the prognostic value and immune signature of NCF2 in pancancer and its relationship with acute myeloid leukemia, Int. Immunopharmacol. 143 (Pt 1) (2024) 113364, https://doi.org/10.1016/j.intimp.2024.113364.

[12] M.S. Ashaq, S. Zhang, M. Xu, Y. Li, B. Zhao, The regulatory role of CD36 in hematopoiesis beyond fatty acid uptake, Life Sci. 339 (2024) 122442, https://doi.org/10.1016/j.lfs.2024.122442.

[13] M.S. Ashaq, Q. Zhou, Z. Li, B. Zhao, Novel targeted therapies in chronic myeloid leukemia, Pharm. Sci. Adv. 2 (2024) 100052, https://doi.org/10.1016/j.pscia.2024.100052.

[14] X. Luo, E. Zheng, L. Wei, H. Zeng, H. Qin, X. Zhang, M. Liao, L. Chen, L. Zhao, X. Z. Ruan, P. Yang, Y. Chen, The fatty acid receptor CD36 promotes HCC progression through activating Src/PI3K/AKT axis-dependent aerobic glycolysis, Cell Death Dis. 12 (4) (2021) 328, https://doi.org/10.1038/s41419-021-03596-w.

[15] Y. Chen, J. Zhang, W. Cui, R.L. Silverstein, CD36, a signaling receptor and fatty acid transporter that regulates immune cell metabolism and fate, J. Exp. Med. 219 (6) (2022), https://doi.org/10.1084/jem.20211314.

[16] W.W. Feng, H.T. Zuppe, M. Kurokawa, The role of CD36 in cancer progression and its value as a therapeutic target, Cells 12 (12) (2023), https://doi.org/10.3390/cells12121605.

[17] J. Li, J. Chen, G. Yang, S. Zhang, P. Li, L. Ye, CD 36 as a therapeutic target in tumor microenvironment and lipid metabolism, anticancer agents, Med. Chem. 25 (7) (2025) 447-459, https://doi.org/10.2174/0118715206353634241111113338.

[18] V. Thorsson, D.L. Gibbs, S.D. Brown, D. Wolf, D.S. Bortone, T.H. Ou Yang, E. PortaPardo, G.F. Gao, C.L. Plaisier, J.A. Eddy, E. Ziv, A.C. Culhane, E.O. Paull, I.K. A. Sivakumar, A.J. Gentles, R. Malhotra, F. Farshidfar, A. Colaprico, J.S. Parker, L. E. Mose, N.S. Vo, J. Liu, Y. Liu, J. Rader, V. Dhankani, S.M. Reynolds, R. Bowlby, A. Califano, A.D. Cherniack, D. Anastassiou, D. Bedognetti, Y. Mokrab, A. M. Newman, A. Rao, K. Chen, A. Krasnitz, H. Hu, T.M. Malta, H. Noushmehr, C. S. Pedamallu, S. Bullman, A.I. Ojesina, A. Lamb, W. Zhou, H. Shen, T.K. Choueiri, J. N. Weinstein, J. Guinney, J. Saltz, R.A. Holt, C.S. Rabkin, A.J. Lazar, J.S. Serody, E. G. Demicco, M.L. Disis, B.G. Vincent, I. Shmulevich, The immune landscape of cancer, Immunity 48 (4) (2018) 812-830.e14, https://doi.org/10.1016/j.immuni.2019.08.004.

[19] R. Bonneville, M.A. Krook, E.A. Kautto, J. Miya, M.R. Wing, H.Z. Chen, J. W. Reeser, L. Yu, S. Roychowdhury, Landscape of microsatellite instability across 39 cancer types, JCO. Precis. Oncol. (2017), https://doi.org/10.1200/PO.17.00073.

[20] R. Beroukhim, C.H. Mermel, D. Porter, G. Wei, S. Raychaudhuri, J. Donovan, J. Barretina, J.S. Boehm, J. Dobson, M. Urashima, K.T. Mc Henry, R.M. Pinchback, A.H. Ligon, Y.J. Cho, L. Haery, H. Greulich, M. Reich, W. Winckler, M.S. Lawrence, B.A. Weir, K.E. Tanaka, D.Y. Chiang, A.J. Bass, A. Loo, C. Hoffman, J. Prensner, T. Liefeld, Q. Gao, D. Yecies, S. Signoretti, E. Maher, F.J. Kaye, H. Sasaki, J. E. Tepper, J.A. Fletcher, J. Tabernero, J. Baselga, M.S. Tsao, F. Demichelis, M. A. Rubin, P.A. Janne, M.J. Daly, C. Nucera, R.L. Levine, B.L. Ebert, S. Gabriel, A. K. Rustgi, C.R. Antonescu, M. Ladanyi, A. Letai, L.A. Garraway, M. Loda, D.G. Beer, L.D. True, A. Okamoto, S.L. Pomeroy, S. Singer, T.R. Golub, E.S. Lander, G. Getz, W.R. Sellers, M. Meyerson, The landscape of somatic copy-number alteration across human cancers, Nature 463 (7283) (2010) 899-905, https://doi.org/10.1038/nature08822.

[21] Z. Tang, B. Kang, C. Li, T. Chen, Z. Zhang, GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis, Nucleic Acids Res. 47 (W1) (2019) W556-w560, https://doi.org/10.1093/nar/gkz430.

[22] F. Chen, D.S. Chandrashekar, S. Varambally, C.J. Creighton, Pan-cancer molecular subtypes revealed by mass-spectrometry-based proteomic characterization of more than 500 human cancers, Nat. Commun. 10 (1) (2019) 5679, https://doi.org/10.1038/s41467-019-13528-0.

[23] E. Cerami, J. Gao, U. Dogrusoz, B.E. Gross, S.O. Sumer, B.A. Aksoy, A. Jacobsen, C. J. Byrne, M.L. Heuer, E. Larsson, Y. Antipin, B. Reva, A.P. Goldberg, C. Sander, N. Schultz, The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data, Cancer Discov. 2 (5) (2012) 401-404, https://doi.org/10.1158/2159-8290.CD-12-0095.

[24] J. Gao, B.A. Aksoy, U. Dogrusoz, G. Dresdner, B. Gross, S.O. Sumer, Y. Sun, A. Jacobsen, R. Sinha, E. Larsson, E. Cerami, C. Sander, N. Schultz, Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal, Sci. Signal. 6 (269) (2013) pl1, https://doi.org/10.1126/scisignal.2004088.

[25] Y. Li, D. Ge, C. Lu, The SMART App: an interactive web application for comprehensive DNA methylation analysis and visualization, Epigenet. Chromatin 12 (1) (2019) 71, https://doi.org/10.1186/s13072-019-0316-3.

[26] T.X. Huang, L. Fu, The immune landscape of esophageal cancer, Cancer Commun. 39 (1) (2019) 79, https://doi.org/10.1186/s40880-019-0427-z.

[27] K. Yoshihara, M. Shahmoradgoli, E. Martínez, R. Vegesna, H. Kim, W. TorresGarcia, V. Treviño, H. Shen, P.W. Laird, D.A. Levine, S.L. Carter, G. Getz, K. Stemke-Hale, G.B. Mills, R.G. Verhaak, Inferring tumour purity and stromal and immune cell admixture from expression data, Nat. Commun. 4 (2013) 2612, https://doi.org/10.1038/ncomms3612.

[28] B. Ru, C.N. Wong, Y. Tong, J.Y. Zhong, S.S.W. Zhong, W.C. Wu, K.C. Chu, C. Y. Wong, C.Y. Lau, I. Chen, N.W. Chan, J. Zhang, TISIDB: an integrated repository portal for tumor-immune system interactions, Bioinformatics 35 (20) (2019) 4200-4202, https://doi.org/10.1093/bioinformatics/btz210.

[29] H. Yuan, M. Yan, G. Zhang, W. Liu, C. Deng, G. Liao, L. Xu, T. Luo, H. Yan, Z. Long, A. Shi, T. Zhao, Y. Xiao, X. Li, CancerSEA: a cancer single-cell state atlas, Nucl. Acid Res. 47 (D1) (2019) D900-d908, https://doi.org/10.1093/nar/gky939.

[30] J. Fu, K. Li, W. Zhang, C. Wan, J. Zhang, P. Jiang, X.S. Liu, Large-scale public data reuse to model immunotherapy response and resistance, Genome Med. 12 (1) (2020) 21, https://doi.org/10.1186/s13073-020-0721-z.

[31] P. Jiang, S. Gu, D. Pan, J. Fu, A. Sahu, X. Hu, Z. Li, N. Traugh, X. Bu, B. Li, J. Liu, G. J. Freeman, M.A. Brown, K.W. Wucherpfennig, X.S. Liu, Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response, Nat. Med. 24 (10) (2018) 1550-1558, https://doi.org/10.1038/s41591-018-0136-1.

[32] Z. Zeng, C.J. Wong, L. Yang, N. Ouardaoui, D. Li, W. Zhang, S. Gu, Y. Zhang, Y. Liu, X. Wang, J. Fu, L. Zhou, B. Zhang, S. Kim, K.B. Yates, M. Brown, G.J. Freeman, R. Uppaluri, R. Manguso, X.S. Liu, TISMO: syngeneic mouse tumor database to model tumor immunity and immunotherapy response, Nucleic Acids Res. 50 (D1) (2022) D1391-d1397, https://doi.org/10.1093/nar/gkab804.

[33] J. Wang, Y. Li, CD 36 tango in cancer: signaling pathways and functions, Theranostics 9 (17) (2019) 4893-4908, https://doi.org/10.7150/thno.36037.

[34] G. Pascual, A. Avgustinova, S. Mejetta, M. Martín, A. Castellanos, C.S. Attolini, A. Berenguer, N. Prats, A. Toll, J.A. Hueto, C. Bescós, L. Di Croce, S.A. Benitah, Targeting metastasis-initiating cells through the fatty acid receptor CD36, Nature 541 (7635) (2017) 41-45, https://doi.org/10.1038/nature20791.

[35] S. Xu, O. Chaudhary, P. Rodríguez-Morales, X. Sun, D. Chen, R. Zappasodi, Z. Xu, A.F.M. Pinto, A. Williams, I. Schulze, Y. Farsakoglu, S.K. Varanasi, J.S. Low, W. Tang, H. Wang, B. McDonald, V. Tripple, M. Downes, R.M. Evans, N. A. Abumrad, T. Merghoub, J.D. Wolchok, M.N. Shokhirev, P.C. Ho, J.L. Witztum, B. Emu, G. Cui, S.M. Kaech, Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8(+) T cells in tumors, Immunity 54 (7) (2021) 1561-1577.e7, https://doi.org/10.1016/j.immuni.2021.05.003.

[36] Q. Sun, W. Zhang, L. Wang, F. Guo, D. Song, Q. Zhang, D. Zhang, Y. Fan, J. Wang, Hypermethylated CD36 gene affected the progression of lung cancer, Gene 678 (2018) 395-406, https://doi.org/10.1016/j.gene.2018.06.101.

[37] M. Deng, X. Cai, L. Long, L. Xie, H. Ma, Y. Zhou, S. Liu, C. Zeng, CD 36 promotes the epithelial-mesenchymal transition and metastasis in cervical cancer by interacting with TGF- β J. Transl. Med. 17 (1) (2019) 352, https://doi.org/10.1186/s12967-019-2098-6.

[38] J. Pan, Z. Fan, Z. Wang, Q. Dai, Z. Xiang, F. Yuan, M. Yan, Z. Zhu, B. Liu, C. Li, CD 36 mediates palmitate acid-induced metastasis of gastric cancer via AKT/GSK-3β/β-catenin pathway, J. Exp. Clin. Cancer Res. 38 (1) (2019) 52, https://doi.org/10.1186/s13046-019-1049-7.

[39] S.J. Im, M. Hashimoto, M.Y. Gerner, J. Lee, H.T. Kissick, M.C. Burger, Q. Shan, J. S. Hale, J. Lee, T.H. Nasti, A.H. Sharpe, G.J. Freeman, R.N. Germain, H.I. Nakaya, H.H. Xue, R. Ahmed, Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy, Nature 537 (7620) (2016) 417-421, https://doi.org/10.1038/nature19330.

[40] I. Siddiqui, K. Schaeuble, V. Chennupati, S.A. Fuertes Marraco, S. Calderon-Copete, D. Pais Ferreira, S.J. Carmona, L. Scarpellino, D. Gfeller, S. Pradervand, S. A. Luther, D.E. Speiser, W. Held, Intratumoral Tcf1(+)PD-1(+)CD8(+) T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy, Immunity 50 (1) (2019) 195-211.e10, https://doi.org/10.1016/j.immuni.2018.12.021.

[41] N.A. Gherardin, S.J. Redmond, H.E.G. McWilliam, C.F. Almeida, K.H.A. Gourley, R. Seneviratna, S. Li, R. De Rose, F.J. Ross, C.V. Nguyen-Robertson, S. Su, M. E. Ritchie, J.A. Villadangos, D.B. Moody, D.G. Pellicci, A.P. Uldrich, D.I. Godfrey, CD36 family members are TCR-independent ligands for CD1 antigen-presenting molecules, Sci. Immunol. 6 (60) (2021), https://doi.org/10.1126/sciimmunol.abg4176.

[42] S.Y. Lim, A.E. Yuzhalin, A.N. Gordon-Weeks, R.J. Muschel, Targeting the CCL2CCR2 signaling axis in cancer metastasis, Oncotarget 7 (19) (2016) 28697-28710, https://doi.org/10.18632/oncotarget.7376.

[43] S. Spranger, R. Bao, T.F. Gajewski, Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity, Nature 523 (7559) (2015) 231-235, https://doi.org/10.1038/nature14404.

[44] J.A. Joyce, D.T. Fearon, T cell exclusion, immune privilege, and the tumor microenvironment, Science 348 (6230) (2015) 74-80, https://doi.org/10.1126/science.aaa6204.

[45] X. Liao, S. Yan, J. Li, C. Jiang, S. Huang, S. Liu, X. Zou, G. Zhang, J. Zou, Q. Liu, CD36 and its role in regulating the tumor microenvironment, Curr. Oncol. 29 (11) (2022) 8133-8145, https://doi.org/10.3390/curroncol29110642.

[46] X. Ma, L. Xiao, L. Liu, L. Ye, P. Su, E. Bi, Q. Wang, M. Yang, J. Qian, Q. Yi, CD36mediated ferroptosis dampens intratumoral CD8(+) T cell effector function and impairs their antitumor ability, Cell. Metab. 33 (5) (2021) 1001-1012.e5, https://doi.org/10.1016/j.cmet.2021.02.015.

[47] H.R. Jin, J. Wang, Z.J. Wang, M.J. Xi, B.H. Xia, K. Deng, J.L. Yang, Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics, J. Hematol. Oncol. 16 (1) (2023) 103, https://doi.org/10.1186/s13045-023-01498-2.

[48] K.E. Pauken, M.A. Sammons, P.M. Odorizzi, S. Manne, J. Godec, O. Khan, A. M. Drake, Z. Chen, D.R. Sen, M. Kurachi, R.A. Barnitz, C. Bartman, B. Bengsch, A. C. Huang, J.M. Schenkel, G. Vahedi, W.N. Haining, S.L. Berger, E.J. Wherry, Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade, Science 354 (6316) (2016) 1160-1165, https://doi.org/10.1186/s13045-023-01498-2.