肠道菌群与抗肿瘤免疫检查点抑制剂关系的研究进展

Research Progress on the Relationship between Gut Microbiota and Anti-Tumor Immune Checkpoint Inhibitors

摘要

肠道菌群在维持局部和全身免疫稳态方面发挥重要作用,并参与肿瘤的发生与发展。此外,肠道菌群还可积极影响抗肿瘤免疫治疗,尤其是免疫检查点抑制剂(ICI)的治疗。肠道菌群组成类型及多样性可直接影响肿瘤免疫治疗效果,并且免疫应答效率能通过补充特定菌群或菌群移植得到改善。这种菌群-免疫之间的相关调控涉及多种机制,如菌群调节先天性或适应性免疫细胞活性、增强肿瘤细胞免疫原性及肠道菌群代谢产物调控宿主基因表达等。本文主要综述肠道菌群参与调控ICI治疗相关证据及潜在分子机制的研究进展,为进一步利用肠道菌群预测、增强ICI疗效提供理论支持。

Abstract

Gut microbiota plays a crucial role in maintaining both local and systemic immune homeostasis and is actively involved in tumor initiation and progression. Moreover, gut microbiota can significantly influence anti-tumor immunotherapy, particularly immune checkpoint inhibitor (ICI) therapy. The composition and diversity of gut microbiota directly impact the efficacy of tumor immunotherapy, and the efficiency of immune responses can be enhanced through supplementation with specific bacterial strains or fecal microbiota transplantation. The regulatory interactions between gut microbiota and immunity involve multiple mechanisms, including modulation of innate and adaptive immune cell activity, enhancement of tumor cell immunogenicity, and regulation of host gene expression via microbial metabolites. This review summarizes recent advances in understanding the role of gut microbiota in modulating ICI therapy, exploring the supporting evidence and underlying molecular mechanisms, with the aim of providing a theoretical basis for leveraging gut microbiota to predict and enhance ICI efficacy.

关键词

肠道菌群 / 肿瘤微环境 / 免疫治疗 / 菌群移植

Key words

gut microbiota / tumor microenvironment / immunotherapy / fecal microbiota transplantation

参考文献

[1] Brown J A, Bashir H, Zeng M Y. Lifelong partners: gut microbiota—immune cell interactions from infancy to old age[J]. Mucosal Immunol, 2025, 18(3): 509-523.

[2] El Leithy A A, Youssef A S E, Nassar A, et al. Long—read 16S rRNA amplicon sequencing reveals microbial characteristics in patients with colorectal adenomas and carcinoma lesions in Egypt[J]. Gut Pathog, 2025, 17(1): 8.

[3] Vétizou M, Pitt J M, Daillère R, et al. Anticancer immunotherapy by CTLA—4 blockade relies on the gut microbiota[J]. Science, 2015, 350(6264): 1079-1084.

[4] Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti—PD—L1 efficacy[J]. Science, 2015, 350(6264): 1084-1089.

[5] Jiang S S, Kang Z R, Chen Y X, et al. The gut microbiome modulate response to immunotherapy in cancer[J]. Sci China Life Sci, 2025, 68(2): 381-396.

[6] Marques de Souza P R, Keenan C M, Wallace L E, et al. T cells regulate intestinal motility and shape enteric neuronal responses to intestinal microbiota[J]. Gut Microbes, 2025, 17(1): 2442528.

[7] Schluter J, Peled J U, Taylor B P, et al. The gut microbiota is associated with immune cell dynamics in humans[J]. Nature, 2020, 588(7837): 303-307.

[8] Jordan A, Carding S R, Hall L J. The early—life gut microbiome and vaccine efficacy[J]. Lancet Microbe, 2022, 3(10): e787-e794.

[9] Gao H Y, Nepovimova E, Adam V, et al. Age—associated changes in innate and adaptive immunity: role of the gut microbiota[J]. Front Immunol, 2024, 15: 1421062.

[10] Georgiev P, Benamar M, Han S, et al. Regulatory T cells in dominant immunologic tolerance[J]. J Allergy Clin Immunol, 2024, 153(1): 28-41.

[11] Arifuzzaman M, Collins N, Guo C J, et al. Nutritional regulation of microbiota—derived metabolites: implications for immunity and inflammation[J]. Immunity, 2024, 57(1): 14-27.

[12] Simpson R C, Shanahan E R, Scolyer R A, et al. Towards modulating the gut microbiota to enhance the efficacy of immune—checkpoint inhibitors[J]. Nat Rev Clin Oncol, 2023, 20(10): 697-715.

[13] Guillot N, Roméo B, Manesh S S, et al. Manipulating the gut and tumor microbiota for immune checkpoint inhibitor therapy: from dream to reality[J]. Trends Mol Med, 2023, 29(11): 897-911.

[14] Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD—1—based immunotherapy against epithelial tumors[J]. Science, 2018, 359(6371): 91-97.

[15] Tinsley N, Zhou C, Tan G, et al. Cumulative antibiotic use significantly decreases efficacy of checkpoint inhibitors in patients with advanced cancer[J]. Oncologist, 2020, 25(1): 55-63.

[16] Pinato D J, Howlett S, Ottaviani D, et al. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer[J]. JAMA Oncol, 2019, 5(12): 1774-1778.

[17] Lurienne L, Cervesi J, Duhalde L, et al. NSCLC immunotherapy efficacy and antibiotic use: a systematic review and meta—analysis[J]. J Thorac Oncol, 2020, 15(7): 1147-1159.

[18] Fessas P, Naeem M, Pinter M, et al. Early antibiotic exposure is not detrimental to therapeutic effect from immunotherapy in hepatocellular carcinoma[J]. Liver Cancer, 2021, 10(6): 583-592.

[19] Mao J Z, Wang D X, Long J Y, et al. Gut microbiome is associated with the clinical response to anti—PD—1 based immunotherapy in hepatobiliary cancers[J]. J Immunother Cancer, 2021, 9(12): e003334.

[20] Derosa L, Routy B, Thomas A M, et al. Intestinal Akkermansia muciniphila predicts clinical response to PD—1 blockade in patients with advanced non—small—cell lung cancer[J]. Nat Med, 2022, 28(2): 315-324.

[21] Matson V, Fessler J, Bao R Y, et al. The commensal microbiome is associated with anti—PD—1 efficacy in metastatic melanoma patients[J]. Science, 2018, 359(6371): 104-108.

[22] Liu L S, Shah K. The potential of the gut microbiome to reshape the cancer therapy paradigm: a review[J]. JAMA Oncol, 2022, 8(7): 1059-1067.

[23] Si W, Liang H, Bugno J, et al. Lactobacillus rhamnosus GG induces cGAS/STING—dependent type Ⅰ interferon and improves response to immune checkpoint blockade[J]. Gut, 2022, 71(3): 521-533.

[24] Kang X, Liu C G, Ding Y Q, et al. Roseburia intestinalis generated butyrate boosts anti—PD—1 efficacy in colorectal cancer by activating cytotoxic CD8+ T cells[J]. Gut, 2023, 72(11): 2112-2122.

[25] Ting N L, Lau H C, Yu J. Cancer pharmacomicrobiomics: targeting microbiota to optimise cancer therapy outcomes[J]. Gut, 2022, 71(7): 1412-1425.

[26] Park E M, Chelvanambi M, Bhutiani N, et al. Targeting the gut and tumor microbiota in cancer[J]. Nat Med, 2022, 28(4): 690-703.

[27] Di Luccia B, Molgora M, Khantakova D, et al. TREM2 deficiency reprograms intestinal macrophages and microbiota to enhance anti—PD—1 tumor immunotherapy[J]. Sci Immunol, 2024, 9(95): eadi5374.

[28] Bae M, Cassilly C D, Liu X X, et al. Akkermansia muciniphila phospholipid induces homeostatic immune responses[J]. Nature, 2022, 608(7921): 168-173.

[29] Chaput N, Lepage P, Coutzac C, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab[J]. Ann Oncol, 2017, 28(6): 1368-1379.

[30] Bessell C A, Isser A, Havel J J, et al. Commensal bacteria stimulate antitumor responses via T cell cross—reactivity[J]. JCI Insight, 2020, 5(8): e135597.

[31] Zhu X Q, Hu M N, Huang X W, et al. Interplay between gut microbial communities and metabolites modulates pan—cancer immunotherapy responses[J]. Cell Metab, 2025, 37(4): 806-823.e6.

[32] Cong J J, Liu P P, Han Z L, et al. Bile acids modified by the intestinal microbiota promote colorectal cancer growth by suppressing CD8+ T cell effector functions[J]. Immunity, 2024, 57(4): 876-889.e11.

[33] McCulloch J A, Davar D, Rodrigues R R, et al. Intestinal microbiota signatures of clinical response and immune—related adverse events in melanoma patients treated with anti—PD—1[J]. Nat Med, 2022, 28(3): 545-556.

[34] Littmann E R, Lee J J, Denny J E, et al. Host immunity modulates the efficacy of microbiota transplantation for treatment of Clostridioides difficile infection[J]. Nat Commun, 2021, 12(1): 755.

[35] Jia D, Wang Q W, Qi Y D, et al. Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan—cancer[J]. Cell, 2024, 187(7): 1651-1665.

[36] Shaikh F Y, Gills J J, Mohammad F, et al. Murine fecal microbiota transfer models selectively colonize human microbes and reveal transcriptional programs associated with response to neoadjuvant checkpoint inhibitors[J]. Cancer Immunol Immunother, 2022, 71(10): 2405-2420.

[37] Routy B, Lenehan J G, Miller W H Jr, et al. Fecal microbiota transplantation plus anti—PD—1 immunotherapy in advanced melanoma: a phase Ⅰ trial[J]. Nat Med, 2023, 29(8): 2121-2132.

[38] Park S R, Kim G, Kim Y, et al. Fecal microbiota transplantation combined with anti—PD—1 inhibitor for unresectable or metastatic solid cancers refractory to anti—PD—1 inhibitor[J]. J Clin Oncol, 2023, 41(16_suppl): 105.

[39] Davar D, Dzutsev A K, McCulloch J A, et al. Fecal microbiota transplant overcomes resistance to anti—PD—1 therapy in melanoma patients[J]. Science, 2021, 371(6529): 595-602.

[40] Baruch E N, Youngster I, Ben—Betzalel G, et al. Fecal microbiota transplant promotes response in immunotherapy—refractory melanoma patients[J]. Science, 2021, 371(6529): 602-609.

[41] Tanoue T, Morita S, Plichta D R, et al. A defined commensal consortium elicits CD8 T cells and anti—cancer immunity[J]. Nature, 2019, 565(7741): 600-605.

[42] Park J S, Gazzaniga F S, Wu M, et al. Targeting PD—L2—RGMb overcomes microbiome—related immunotherapy resistance[J]. Nature, 2023, 617(7960): 377-385.

[43] Gopalakrishnan V, Spencer C N, Nezi L, et al. Gut microbiome modulates response to anti—PD—1 immunotherapy in melanoma patients[J]. Science, 2018, 359(6371): 97-103.

[44] Fluckiger A, Daillère R, Sassi M, et al. Cross—reactivity between tumor MHC class I—restricted antigens and an enterococcal bacteriophage[J]. Science, 2020, 369(6506): 936-942.

[45] Naghavian R, Faigle W, Oldrati P, et al. Microbial peptides activate tumour—infiltrating lymphocytes in glioblastoma[J]. Nature, 2023, 617(7962): 807-817.

[46] Zhang L, Jiang L, Yu L, et al. Inhibition of UBA6 by inosine augments tumour immunogenicity and responses[J]. Nat Commun, 2022, 13(1): 5413.

[47] Bird L. Microbial metabolite boosts immunotherapy[J]. Nat Rev Immunol, 2020, 20(11): 648-649.

[48] Mager L F, Burkhard R, Pett N, et al. Microbiome—derived inosine modulates response to checkpoint inhibitor immunotherapy[J]. Science, 2020, 369(6510): 1481-1489.

[49] He Y, Fu L H, Li Y P, et al. Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8+ T cell immunity[J]. Cell Metab, 2021, 33(5): 988-1000.

基金资助

国家自然科学基金项目(81974382)

湖北省自然科学基金项目(2024AFB230)