Antibiotic use and the efficacy of immune checkpoint inhibitors in cancer patients: a pooled analysis of 2740 cancer patients
Open accessAbstract
The gut microbiota plays a critical role in the anti-tumor immune response. There is increasing data showing that antibiotics (ATBs) change the composition of the gut microbiota and affect the efficacy of immune checkpoint inhibitors (ICIs). However, this is the first meta-analysis to evaluate the association between ATB use and ICI efficacy in cancer patients to provide a better understanding of the strength of this association. We performed a literature search for relevant studies that evaluated the relationship between ATB use and ICI efficacy using the PubMed, Embase, and conference databases. The primary outcomes consisted of overall survival (OS) and progression-free survival (PFS) measured by hazard ratios (HR) and corresponding 95% confidence intervals (CI). Subgroup and sensitivity analyses were also performed. A total of 19 eligible studies comprising 2,740 cancer patients treated with ICIs were included in the analysis. Our results indicated that ATB use was negatively associated with OS in cancer patients (HR = 2.37; 95% CI = 2.05–2.75; P < .001), without heterogeneity (I2 = 0.0%; P = .851). Moreover, ATB use significantly reduced PFS in patients treated with ICIs (HR = 1.84; 95% CI = 1.49–2.26; P < .001; I2 = 56.2%). Similar results were obtained in the subgroup analyses stratified by the time of ATB use and cancer type. Sensitivity analyses confirmed the stability of our results. Therefore, the findings of our meta-analysis indicated that ATB use is negatively associated with OS and PFS in cancer patients treated with ICI immunotherapy.
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A growing body of clinical evidence indicates that systemic antibiotics eliminate the benefit of immune checkpoint blockade and reduce patient survival.
“However, increasing clinical evidence suggests that systemic antibiotics abolish immune checkpoint blockade efficacy and decrease patient survival (133, 136, 137).”
From The microbiome and human cancer (2021) · cites this paper as [136]
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“Finally, 19 studies were included in our quantitative analysis (Figure 1).(10,12-29)”
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“This meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA) statement (Supplementary File 1).(36) The primary outcome was OS and secondary outcome was PFS, and the association between ATB use and ICI efficacy was measured by HR with the correspondi…”
MethodBiomarkers for predicting efficacy of PD-1/PD-L1 inhibitors
Yi, M., Jiao, D., Xu, H., Liu, Q., Zhao, W., Han, X., & Wu, K. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0864-3 · Cited by 756 · cited 1× · see citing works
“, PD-L1 expression, tumor mutational burden, tumor infiltrating lymphocytes, mismatch repair deficiency, and high microsatellite instability); however, the predictive precision of such potential biomarkers remains limited.(5,6) Thus, it is critical to explore reliable predictors to improve the clinical response to ICI…”
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“A random effect model was used to pool the HRs if the heterogeneity was significant; otherwise, a fixed effects model was used.(37) Begg’s and Egger’s tests were used to evaluate publication bias, and a trim-and-fill analysis was performed to evaluate the effect of potential publication bias on an outcome if the p val…”
MethodIntestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children
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“Moreover, it has been is well-documented that antibiotics (ATBs) can alter the diversity and composition of the commensal gut microbiota.(11) Thus, researchers hypothesize that dysbiosis of the gut microbiota caused by ATBs may be associated with resistance to ICI immunotherapy and have a negative impact on the effica…”
BackgroundDevelopment of immuno-oncology drugs — from CTLA4 to PD1 to the next generations
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“Immune checkpoint inhibitors (ICIs) that target programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), have altered the therapeutic landscape and have become an attractive treatment strategy in several malignancies due to their high efficacy an…”
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“, PD-L1 expression, tumor mutational burden, tumor infiltrating lymphocytes, mismatch repair deficiency, and high microsatellite instability); however, the predictive precision of such potential biomarkers remains limited.(5,6) Thus, it is critical to explore reliable predictors to improve the clinical response to ICI…”
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“Finally, 19 studies were included in our quantitative analysis (Figure 1).(10,12-29)”
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“Finally, 19 studies were included in our quantitative analysis (Figure 1).(10,12-29)”
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Impact of prior antibiotic use on the efficacy of nivolumab for non‑small cell lung cancer
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“Finally, 19 studies were included in our quantitative analysis (Figure 1).(10,12-29)”
A Microtubule Interactome: Complexes with Roles in Cell Cycle and Mitosis
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Antibiotic Use Does Not Appear to Influence Response to Nivolumab
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“Indeed, our subgroup analyses also indicated that the HR for ATB use within 1 month before ICI was greater than that within 2 months before ICI.”
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“Finally, 19 studies were included in our quantitative analysis (Figure 1).(10,12-29)”
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“Of the eligible studies, eight studies were complete cohort studies(10,12,16,17,24,26,27,29) and 11 studies provided only an abstract.(13-15,18-23,25,28) The main characteristics of the included studies are listed in Table 1.”
BackgroundImmune checkpoint inhibitors in older adults
Elias, R., Morales, J., Rehman, Y., & Khurshid, H. (2016) · Current Oncology Reports · doi:10.1007/s11912-016-0534-9 · Cited by 59 · cited 1× · see citing works
“Immune checkpoint inhibitors (ICIs) that target programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), have altered the therapeutic landscape and have become an attractive treatment strategy in several malignancies due to their high efficacy an…”
BackgroundMechanisms of Primary and Secondary Resistance to Immune Checkpoint Inhibitors in Cancer
Seto, T., Sam, D. L., & Pan, M. (2019) · Medical Sciences · doi:10.3390/medsci7020014 · Cited by 51 · cited 1× · see citing works
“However, in clinical practice, the clinical efficacy of ICIs is highly variable among cancer patients, and a considerable proportion of patients still progress with disease or relapse due to ICI resistance and limited efficacy.(3,4) Recently, researchers have sought to identify prognostic and predictive biomarkers ass…”
BackgroundKnox, J. J., Barrios, C. H., Kim, T. M., Cosgriff, T. M., Srimuninnimit, V., Pittman, K. B., Sabbatini, R., Rha, S. Y., Flaig, T. W., Page, R. D., et al. (2018) · Annals of Oncology · doi:10.1093/annonc/mdx807 · Cited by 27 · see citing works
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“A total of 14 studies used anti-PD-1/PD-L1 inhibitors,(10,12,13,15,16,18,20,22-25,27-29) three studies used anti-PD-1/PD-L1 inhibitors and/or anti-CTLA-4 inhibitors,(17,21,26) and two studies did not report the type of ICI drug.(14,19) Of the eligible studies, eight studies were complete cohort studies(10,12,16,17,24,…”
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“Of the eligible studies, eight studies were complete cohort studies(10,12,16,17,24,26,27,29) and 11 studies provided only an abstract.(13-15,18-23,25,28) The main characteristics of the included studies are listed in Table 1.”
BackgroundAntibiotic use and overall survival in lung cancer patients receiving nivolumab.
Do, T. P., Hegde, A. M., Cherry, C. R., Stroud, C. R. G., Sharma, N. J., Cherukuri, S. D., Bowling, M., & Walker, P. R. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2018.36.15_suppl.e15109 · Cited by 22 · cited 2× · see citing works
“Of the eligible studies, eight studies were complete cohort studies(10,12,16,17,24,26,27,29) and 11 studies provided only an abstract.(13-15,18-23,25,28) The main characteristics of the included studies are listed in Table 1.”
BackgroundAntibiotic use and outcomes with systemic therapy in metastatic renal cell carcinoma (mRCC).
Lalani, A. A., Xie, W., Lin, X., Steinharter, J. A., Martini, D. J., Duquette, A., Bossé, D., McKay, R. R., Simantov, R., Wei, X. X., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2018.36.6_suppl.607 · Cited by 16 · cited 2× · see citing works
“Of the eligible studies, eight studies were complete cohort studies(10,12,16,17,24,26,27,29) and 11 studies provided only an abstract.(13-15,18-23,25,28) The main characteristics of the included studies are listed in Table 1.”
BackgroundAgarwal, A., Pond, G. R., Curran, C. R., Nassar, A. H., Nuzzo, P. V., Kumar, V., McGregor, B. A., Wei, X. X., Harshman, L. C., Choueiri, T. K., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.2019.37.7_suppl.435 · Cited by 13 · cited 2× · see citing works
“Of the eligible studies, eight studies were complete cohort studies(10,12,16,17,24,26,27,29) and 11 studies provided only an abstract.(13-15,18-23,25,28) The main characteristics of the included studies are listed in Table 1.”
BackgroundPinato, D. J., Howlett, S., Ottaviani, D., Urus, H., Patel, A., Mineo, T., Brock, C. S., Power, D., Hatcher, O., Falconer, A., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.2019.37.8_suppl.147 · Cited by 13 · cited 2× · see citing works
“Of the eligible studies, eight studies were complete cohort studies(10,12,16,17,24,26,27,29) and 11 studies provided only an abstract.(13-15,18-23,25,28) The main characteristics of the included studies are listed in Table 1.”
BackgroundSchett, A., Rothschild, S. I., Mauti, L. A., Schmid, S., Appenzeller, C., Fontecedro, A. C., Frueh, M., & Joerger, M. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz063.055 · Cited by 9 · cited 2× · see citing works
“Of the eligible studies, eight studies were complete cohort studies(10,12,16,17,24,26,27,29) and 11 studies provided only an abstract.(13-15,18-23,25,28) The main characteristics of the included studies are listed in Table 1.”
BackgroundRounis, K., Papadaki, C., Makrakis, D. A., Monastirioti, A. A., Vamvakas, L., Kalbakis, K., Mavroudis, D., & Aggelaki, S. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz063.064 · Cited by 9 · cited 3× · see citing works
“A total of 14 studies used anti-PD-1/PD-L1 inhibitors,(10,12,13,15,16,18,20,22-25,27-29) three studies used anti-PD-1/PD-L1 inhibitors and/or anti-CTLA-4 inhibitors,(17,21,26) and two studies did not report the type of ICI drug.(14,19) Of the eligible studies, eight studies were complete cohort studies(10,12,16,17,24,…”
BackgroundClinical association of antibiotics in immune checkpoint inhibitors for advanced cancer treatment
Kim, H., & Kim, I.-H. (2018) · Annals of Oncology · doi:10.1093/annonc/mdy433.002 · Cited by 7 · cited 2× · see citing works
“Of the eligible studies, eight studies were complete cohort studies(10,12,16,17,24,26,27,29) and 11 studies provided only an abstract.(13-15,18-23,25,28) The main characteristics of the included studies are listed in Table 1.”
BackgroundSwami, U., Monga, V., Knutson, T. M., Bossler, A., Zakharia, Y., & Milhem, M. M. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2018.36.15_suppl.e21527 · Cited by 5 · cited 2× · see citing works
“Of the eligible studies, eight studies were complete cohort studies(10,12,16,17,24,26,27,29) and 11 studies provided only an abstract.(13-15,18-23,25,28) The main characteristics of the included studies are listed in Table 1.”
Background
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The microbiome and human cancer
Sepich-Poore, G. D., Zitvogel, L., Straussman, R., Hasty, J., Wargo, J. A., & Knight, R. (2021) · Science · doi:10.1126/science.abc4552 · Cited by 1,332 · see citing works
(2023) · doi:10.1038/s41392-022-01304-4 · Cited by 460 · see citing works
“Increasing clinical data suggest that systemic use of antibiotics can lead to less effective immune checkpoint inhibitors.(235,236) In addition, several studies in patients with lung, colon, and pancreatic cancer have shown that removal of the tumor microbiota can enhance the inflammatory process of the tumor, inhibit…”
Backgroundγδ T cells: origin and fate, subsets, diseases and immunotherapy
Hu, Y., Hu, Q., Li, Y., Lu, L., Xiang, Z., Yin, Z., Kabelitz, D., & Wu, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01653-8 · Cited by 395 · see citing works
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“Probiotic CBT improved ICB efficacy in antibiotic-treated patients Antibiotic therapy before the start of ICB therapy reduces response to ICB (1, 3, 4, 7).”
BackgroundResultInfluentialIntestinal microbiota influences clinical outcome and side effects of early breast cancer treatment
Terrisse, S., Derosa, L., Iebba, V., Ghiringhelli, F., Vaz-Luis, I., Kroemer, G., Fidelle, M., Christodoulidis, S., Segata, N., Thomas, A. M., et al. (2021) · Cell Death & Differentiation · doi:10.1038/s41418-021-00784-1 · Cited by 172 · see citing works
Gut microbiota shapes cancer immunotherapy responses
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“Preclinical and clinical studies suggest that antibiotic use, particularly broad-spectrum antibiotics, may impair ICI ef fi cacy (Table 2) 95, 207 – 228 .”
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Mechanisms of resistance to immune checkpoint inhibitors in melanoma: What we have to overcome?
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Gut microbiota-mediated immunomodulation in tumor
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“Huang et al. 2019 [132] A meta-analysis included 33 eligible studies comprising 5565 cancer patients ICI (anti-PD−/PD-L1 or anti-CTLA-4) alone or combined with chemotherapy/targeted therapy.”
BackgroundAghamajidi, A., & Vareki, S. M. (2022) · Cancers · doi:10.3390/cancers14153563 · Cited by 102 · see citing works
Takada, K., Shimokawa, M., Takamori, S., Shimamatsu, S., Hirai, F., Tagawa, T., Okamoto, T., Hamatake, M., Tsuchiya‐Kawano, Y., Otsubo, K., et al. (2021) · International Journal of Cancer · doi:10.1002/ijc.33557 · Cited by 100 · see citing works
“Recent studies showed that the gastrointestinal microbiota might play an important and significant role in the response to ICIs.14-16 Some reports revealed associations between drugs associated with gastrointestinal dysbiosis and bacterial richness, antibiotics and proton pump inhibitors (PPIs), and the efficacy of IC…”
BackgroundInfluentialTomita, Y., Goto, Y., Sakata, S., Imamura, K., Minemura, A., Oka, K., Hayashi, A., Jodai, T., Akaike, K., Anai, M., et al. (2022) · OncoImmunology · doi:10.1080/2162402x.2022.2081010 · Cited by 100 · see citing works
“Retrospective studies have reproducibly shown that exposure to antibiotics prior to receiving ICB therapy is especially detrimental to the clinical outcome.(4,6,9,24,25) Thus, we investigated the influence of antibiotic therapy within 60 days before the start of ICB therapy on clinical outcomes in patients who receive…”
BackgroundCan we harness the microbiota to enhance the efficacy of cancer immunotherapy?
Finlay, B. B., Goldszmid, R., Honda, K., Trinchieri, G., Wargo, J., & Zitvogel, L. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-0374-6 · Cited by 81 · see citing works
Tsikala-Vafea, M., Belani, N., Vieira, K., Khan, H., & Farmakiotis, D. (2021) · International Journal of Infectious Diseases · doi:10.1016/j.ijid.2021.03.063 · Cited by 76 · see citing works
The gut microbiome and efficacy of cancer immunotherapy
Roviello, G., Iannone, L. F., Bersanelli, M., Mini, E., & Catalano, M. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107973 · Cited by 75 · see citing works
Local tumor microbial signatures and response to checkpoint blockade in non-small cell lung cancer
Boesch, M., Baty, F., Albrich, W. C., Flatz, L., Rodriguez, R., Rothschild, S. I., Joerger, M., Früh, M., & Brutsche, M. H. (2021) · OncoImmunology · doi:10.1080/2162402x.2021.1988403 · Cited by 74 · see citing works
Antibiotic use influences outcomes in advanced pancreatic adenocarcinoma patients
Mohindroo, C., Hasanov, M., Rogers, J. E., Dong, W., Prakash, L. R., Baydogan, S., Mizrahi, J. D., Overman, M. J., Varadhachary, G. R., Wolff, R. A., et al. (2021) · Cancer Medicine · doi:10.1002/cam4.3870 · Cited by 73 · see citing works
Crespin, A., Bescop, C. L., de Gunzburg, J., Vitry, F., Zalcman, G., Cervesi, J., & Bandinelli, P.-A. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1075593 · Cited by 73 · see citing works
Albandar, H. J., Fuqua, J. L., Albandar, J. M., Safi, S. U. D., Merrill, S. A., & Ma, P. C. (2021) · Cancers · doi:10.3390/cancers13050989 · Cited by 71 · see citing works
“However, there is growing literature that suggests antibiotic use in this period adversely affects survival, although we were unable to demonstrate this in our study [19].”
ResultThe interplay of obesity, gut microbiome and diet in the immune check point inhibitors therapy era
Spyrou, N., Vallianou, N. G., Kadillari, J., & Dalamaga, Μ. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.05.008 · Cited by 65 · see citing works
Gut Microbiome Modulates Response to Cancer Immunotherapy
Khan, M. A. W., Ologun, G. O., Arora, R., McQuade, J. L., & Wargo, J. A. (2020) · Digestive Diseases and Sciences · doi:10.1007/s10620-020-06111-x · Cited by 66 · see citing works
McQuade, J. L., Ologun, G. O., Arora, R., & Wargo, J. A. (2020) · Current Oncology Reports · doi:10.1007/s11912-020-00913-y · Cited by 63 · see citing works
Powell, N., Ibraheim, H., Raine, T., Speight, A., Papa, S., Brain, O., Green, M., Samaan, M., Spain, L. A., Yousaf, N., et al. (2020) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(20)30014-5 · Cited by 63 · see citing works
Gut microbiota: impacts on gastrointestinal cancer immunotherapy
Lau, H. C.-H., Sung, J. J. �., & Yu, J. Q. (2021) · Gut Microbes · doi:10.1080/19490976.2020.1869504 · Cited by 56 · see citing works
“conducted a dedicated meta-analysis to pool all data from 19 relevant publications comprising a total of 2,740 cancer patients.(77) Statistically significant reduction in PFS and overall survival were observed when comparing blockade-treated patients with the use of antibiotics to those without regardless of the cance…”
MethodUrinary microbiota and bladder cancer: A systematic review and a focus on uropathogens
Yacouba, A., Alou, M. T., Lagier, J., Dubourg, G., & Raoult, D. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.12.010 · Cited by 57 · see citing works
Yang, M., Wang, Y., Yuan, M., Tao, M., Kong, C., Li, H., Tong, J., Zhu, H., & Yan, X. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106876 · Cited by 57 · see citing works
Self-citationCapula, M., Perán, M., Xu, G., Donati, V. L., Yee, D., Gregori, A., Assaraf, Y. G., Giovannetti, E., & Deng, D. (2022) · Drug Resistance Updates · doi:10.1016/j.drup.2022.100864 · Cited by 56 · see citing works
Intratumoral bacteria are an important “accomplice” in tumor development and metastasis
Wang, G., He, X., & Wang, Q. (2022) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2022.188846 · Cited by 51 · see citing works
Mitochondria and Antibiotics: For Good or for Evil?
Suarez-Rivero, J. M., Pastor‐Maldonado, C. J., Povea-Cabello, S., Álvarez-Córdoba, M., Villalón-García, I., Talaverón-Rey, M., Suárez-Carrillo, A., Munuera-Cabeza, M., & Sánchez-Alcázar, J. A. (2021) · Biomolecules · doi:10.3390/biom11071050 · Cited by 51 · see citing works
“This negative impact was proven to occur irrespective of the cancer type and the moment of antibiotic treatment application [82].”
BackgroundUeda, K., Yonekura, S., Ogasawara, N., Matsunaga, Y., Hoshino, R., Kurose, H., Chikui, K., Uemura, K., Nakiri, M., Nishihara, K., et al. (2019) · Anticancer Research · doi:10.21873/anticanres.13836 · Cited by 50 · see citing works
Zhou, J., Huang, G., Wong, W.-C., Hu, D., Zhu, J.-W., Li, R., & Zhou, H. K. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.968729 · Cited by 48 · see citing works
Roccuzzo, G., Moirano, G., Fava, P., Maule, M. M., Ribero, S., & Quaglino, P. (2023) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2023.02.010 · Cited by 48 · see citing works
Petrelli, F., Iaculli, A., Signorelli, D., Ghidini, A., Dottorini, L., Perego, G., Ghidini, M., Zaniboni, A., Gori, S., & Inno, A. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9051458 · Cited by 47 · see citing works
“A recently published paper by Huang and colleagues had the same goal of the present meta-analysis but with a less updated literature search, and about half of the included papers were congress abstract forms but they came to a similar conclusion [27].”
ResultThe role of gut microbiome in modulating response to immune checkpoint inhibitor therapy in cancer
Naqash, A. R., Kihn-Alarcón, A. J., Stavraka, C., Kerrigan, K. C., Vareki, S. M., Pinato, D. J., & Puri, S. (2021) · Annals of Translational Medicine · doi:10.21037/atm-20-6427 · Cited by 47 · see citing works
“Retrospective clinical data suggests that antibiotic use prior to ICPI can reduce the effectiveness of these agents, likely through altered composition of the gut microbiome (5).”
BackgroundThe impact of the gut microbiome on tumor immunotherapy: from mechanism to application strategies
Guo, C., Kong, L., Xiao, L., Liu, K., Cui, H., Xin, Q., Gu, X., Jiang, C., & Wu, J. (2023) · Cell & Bioscience · doi:10.1186/s13578-023-01135-y · Cited by 46 · see citing works
Nyein, A., Bari, S., Hogue, S., Zhao, Y., Maller, B., Sha, S. T., Gómez, M. F. L., Rollison, D. E. M., & Robinson, L. A. (2022) · BMC Cancer · doi:10.1186/s12885-022-09210-2 · Cited by 45 · see citing works
Microbiome Integrity Enhances the Efficacy and Safety of Anticancer Drug
Mafe, A. N., & Büsselberg, D. (2025) · Biomedicines · doi:10.3390/biomedicines13020422 · Cited by 46 · see citing works
Acquired Resistance to PD-1/PD-L1 Blockade in Lung Cancer: Mechanisms and Patterns of Failure
Pathak, R., Pharaon, R. R., Mohanty, A. R., Villaflor, V. M., Salgia, R., & Massarelli, E. (2020) · Cancers · doi:10.3390/cancers12123851 · Cited by 45 · see citing works
Kubeček, O., Paterová, P., & Novosadová, M. (2021) · Life · doi:10.3390/life11121387 · Cited by 42 · see citing works
Li, C., Xia, Z., Li, A., & Meng, J. (2020) · Annals of Translational Medicine · doi:10.21037/atm-20-7498 · Cited by 42 · see citing works
“therapeutic outcomes, as the diversity and abundance of the gut microbiome are associated with broad spectrum antibiotics (6,7).”
Facts and Hopes for Gut Microbiota Interventions in Cancer Immunotherapy
Davar, D., & Zarour, H. M. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-1129 · Cited by 40 · see citing works
Synthetic and Biogenic Materials for Oral Delivery of Biologics: From Bench to Bedside
Ding, S., Alexander, E., Liang, H., Kulchar, R. J., SINGH, R. K., Herzog, R. W., Daniell, H., & Leong, K. W. (2025) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00482 · Cited by 42 · see citing works
Larionova, I., Patysheva, M. R., Iamshchikov, P. S., Kazakova, E., Казакова, А., Rakina, M. A., Grigoryeva, E. S., Тарасова, А. С., Afanasiev, S. G., Bezgodova, N. V., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1080501 · Cited by 39 · see citing works
“In rectal cancer, the percentage of CD14+CD16monocytes was increased in patients with M-positive status, compared to M-negative status (85,66 (70,18-93,7) vs.”
ResultInfluentialInfections and Immunotherapy in Lung Cancer: A Bad Relationship?
Belluomini, L., Caldart, A., Avancini, A., Dodi, A., Trestini, I., Kadrija, D., Sposito, M., Tregnago, D., Casali, M., Riva, S. T., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms22010042 · Cited by 39 · see citing works
Su, X., Li, J., Xu, X., Ye, Y., Wang, C., Pang, G., Liu, W., Liu, A., Zhao, C., & Hao, X. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05552-6 · Cited by 41 · see citing works
“Typically, antibiotics disrupt normal gut microbial homeostasis, leading to primary resistance to ICIs treatment [238, 247].”
BackgroundWang, M., Zhang, L., Chang, W., & Zhang, Y. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1096551 · Cited by 41 · see citing works
Guillot, N., Roméo, B., Manesh, S. S., Milano, G., Brest, P., Zitvogel, L., Hofman, P., & Mograbi, B. (2023) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2023.08.004 · Cited by 36 · see citing works
The role of the symbiotic microecosystem in cancer: gut microbiota, metabolome, and host immunome
Xue, X., Li, R., Chen, Z., Li, G., Liu, B., Guo, S., Yue, Q., Yang, S., Xie, L., Zhang, Y., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1235827 · Cited by 36 · see citing works
Self-citationSilver, N. L., Dai, J., Kerr, T. D., Altemus, J. B., Garg, R. R., Simmons, H. L., Alban, T. J., Noël‐Romas, L., Makarov, V., Shih, D. J. H., et al. (2026) · Nature Cancer · doi:10.1038/s43018-025-01067-1 · Cited by 36 · see citing works
Velikova, T. V., Krastev, B. M., Lozenov, S., Gencheva, R., Peshevska-Sekulovska, M., Nikolaev, G., & Peruhova, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041754 · Cited by 35 · see citing works
Kulkarni, A. A., Ebadi, M., Zhang, S., Meybodi, M. A., Ali, A. M., DeFor, T. E., Shanley, R., Weisdorf, D. J., Ryan, C. J., Vasu, S., et al. (2020) · ESMO Open · doi:10.1136/esmoopen-2020-000803 · Cited by 34 · see citing works
Therapeutic potential of microbial modulation in pancreatic cancer
Chandra, V., & McAllister, F. M. (2021) · Gut · doi:10.1136/gutjnl-2019-319807 · Cited by 33 · see citing works
“57 Several preclinical studies have also reported on the negative effects of concomitant use of antibiotics and immunotherapy.”
BackgroundIntratumour microbiome of pancreatic cancer
Guan, S.-W., Lin, Q., & Yu, H. (2023) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v15.i5.713 · Cited by 33 · see citing works
Impact of antibiotic treatment on immunotherapy response in women with recurrent gynecologic cancer
Chambers, L., Michener, C. M., Rose, P. G., Reizes, O., Yao, M., & Vargas, R. (2021) · Gynecologic Oncology · doi:10.1016/j.ygyno.2021.01.015 · Cited by 33 · see citing works
Effects of Concomitant Antibiotics Use on Immune Checkpoint Inhibitor Efficacy in Cancer Patients
Jiang, S., Geng, S., Chen, Q., Zhang, C., Cheng, M., Yu, Y., Zhang, S., Shi, N., & Dong, M. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.823705 · Cited by 31 · see citing works
Xin, Y., Liu, C., Zang, D., & Chen, J. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1343450 · Cited by 30 · see citing works
Merali, N., Chouari, T. A. M., Kayani, K., Rayner, C. J., Jiménez, J. I., Krell, J., Giovannetti, E., Bagwan, I., Relph, K., Rockall, T., et al. (2022) · Cancers · doi:10.3390/cancers14041020 · Cited by 28 · see citing works
Golonka, R., & Vijay-Kumar, M. (2021) · Advances in Cancer Research · doi:10.1016/bs.acr.2020.10.004 · Cited by 21 · see citing works
He, J., Li, H., Jia, J., Liu, Y., Zhang, N., Wang, R., Qu, W., Liu, Y., & Jia, L. (2023) · Molecular Biomedicine · doi:10.1186/s43556-023-00157-9 · Cited by 28 · see citing works
“Clinical evidence has shown that antibiotic treatment reduces the efficacy of immune checkpoint inhibitors and patient survival rates [210, 211].”
BackgroundKaramanolis, N. N., Kounatidis, D. C., Vallianou, N. G., Dimitriou, K., Tsaroucha, E., Tsioulos, G., Anastasiou, I. A., Mavrothalassitis, E., Karampela, Ι., & Dalamaga, Μ. (2024) · Antibiotics · doi:10.3390/antibiotics14010009 · Cited by 24 · see citing works
“A meta-analysis of 2740 cancer patients treated with ICIs found that antibiotic use before or during therapy was associated with reduced overall survival (OS) and progression-free survival (PFS) [144].”
Gut Bacteria—Not for the Faint of Heart
Mandelbaum, N., Gefen, T., & Geva‐Zatorsky, N. (2020) · Cell Host & Microbe · doi:10.1016/j.chom.2019.12.011 · Cited by 24 · see citing works
Intratumor microbiota: a novel tumor component
Gong, Y., Huang, X., Wang, M., & Liang, X. (2023) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-023-04576-7 · Cited by 24 · see citing works
“There is also clinical evidence that systemic antibiotics abolish the effects of immune checkpoint blockade and reduce patient survival (Derosa et al. 2018; Huang et al. 2019; Pinato et al. 2019).”
BackgroundSelf-citationAntibiotic Resistance Risk with Oral Tetracycline Treatment of Acne Vulgaris
Swallow, M. A., Fan, R., Cohen, J. M., & Bunick, C. G. (2022) · Antibiotics · doi:10.3390/antibiotics11081032 · Cited by 23 · see citing works
The Gut Microbiome and Pancreatic Cancer Development and Treatment
Attebury, H., & Daley, D. (2023) · The Cancer Journal · doi:10.1097/ppo.0000000000000647 · Cited by 23 · see citing works
Antibiotics, cancer risk and oncologic treatment efficacy: a practical review of the literature
Lopes, M. S. M., Machado, L. M., Silva, P. A. I. A., Uchiyama, A. A. T., Yen, C. T., Ricardo, E. D., Mutão, T. S., Pimento, J. R., Shimba, D. S., Hanriot, R. D. M., et al. (2020) · ecancermedicalscience · doi:10.3332/ecancer.2020.1106 · Cited by 24 · see citing works
“Subgroup analysis on the type of ICI revealed a negative impact on all drugs and combinations [68].”
BackgroundDivergent tumor immunity determined by bacteria-cancer cell engagement
Yao, B., Liu, X.-M., Ruan, K., Fang, X., Jiang, C., Bian, W., Guo, Y., Zhu, X., Shang, Z., Hu, T., et al. (2026) · Cell · doi:10.1016/j.cell.2025.12.044 · Cited by 25 · see citing works
The cure from within? a review of the microbiome and diet in melanoma
Kumar, P. R., Brazel, D., DeRogatis, J. M., Goldstein, J. B., Whiteson, K., Chow, W. A., Tinoco, R., & Moyers, J. T. (2022) · Cancer and Metastasis Reviews · doi:10.1007/s10555-022-10029-3 · Cited by 22 · see citing works
“26); however, patient level factors were not controlled for in this analysis[69].”
BackgroundZapata, M. E. S., Pellitero, A. M., Isla, D., Gálvez, E. H., Ruiz, M. G., Sesma, A., Barbero-Herranz, R., Galeano, J., del Campo, R., Ocáriz, M., et al. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e33684 · Cited by 20 · see citing works
“In view of this discrepancy in response, attempts have been made to identify therapy-predictive biomarker response [4,5], with some previous studies suggesting the relevance of host-related factors, such as the microbiota, which has been directly linked to ICI effectiveness [6,7].”
BackgroundResultGut microbiota: a potential target for improved cancer therapy
Zhao, M., Jiang, G., Zhou, H., Li, J., Xiang, W., Li, S., Wang, H., & Zhou, J. (2022) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-022-04546-5 · Cited by 19 · see citing works
Alshammari, K. M., Alotaibi, F., Alsugheir, F., Aldawoud, M., Alolayan, A. A. M., Algarni, M., Sabatin, F., Mohammad, M. F., Alosaimi, A., Sanai, F. M., et al. (2023) · Cancers · doi:10.3390/cancers16010133 · Cited by 19 · see citing works
“However, not all patients benefit from the treatment, and our study, along with others [25–29], suggests that the use of antibiotics concurrently with ICI could contribute to reduced overall survival.”
Uncovering the role of the gut microbiota in immune checkpoint blockade therapy: A mini-review
Halsey, T. M., Ologun, G. O., Wargo, J. A., & Jenq, R. R. (2020) · Seminars in Hematology · doi:10.1053/j.seminhematol.2020.05.002 · Cited by 19 · see citing works
“A meta-analysis of published clinical data showed that antibiotic use reduced overall survival and progression-free survival in a majority of the profiled cases (13).”
MethodImmuno-oncology-microbiome axis of gastrointestinal malignancy
Lin, Q., Guan, S.-W., & Yu, H. (2023) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v15.i5.757 · Cited by 18 · see citing works
Michaelidou, K., Agelaki, S., & Mavridis, K. (2020) · Expert Review of Molecular Diagnostics · doi:10.1080/14737159.2020.1724785 · Cited by 17 · see citing works
Classic versus innovative strategies for immuno-therapy in pancreatic cancer
Formelli, M. G., Palloni, A., Tavolari, S., Deiana, C., Andrini, E., Marco, M. D., Campana, D., Lamberti, G., & Brandi, G. (2025) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2025.115671 · Cited by 15 · see citing works
Huang, L., Chen, X., Zhou, L. Q., Xu, Q., Xie, J., Zhan, P., Lv, T., & Song, Y. (2021) · Annals of Palliative Medicine · doi:10.21037/apm-20-2076 · Cited by 15 · see citing works
Self-citationAnalysis of interactions of immune checkpoint inhibitors with antibiotics in cancer therapy
Li, Y., Wang, S., Lin, M., Hou, C., Li, C., & Li, G. (2022) · Frontiers of Medicine · doi:10.1007/s11684-022-0927-0 · Cited by 15 · see citing works
The role of the microbiome in pancreatic oncogenesis
Daley, D. (2022) · International Immunology · doi:10.1093/intimm/dxac036 · Cited by 14 · see citing works
Zhang, W., Zhang, J., Liu, T., Xing, J., Zhang, H., Wang, D., & Tang, D. (2022) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-022-04081-3 · Cited by 14 · see citing works
Wardill, H. R., Chan, R. J., Chan, A., Keefe, D. M. K., Costello, S. P., & Hart, N. H. (2022) · Supportive Care in Cancer · doi:10.1007/s00520-022-06948-0 · Cited by 13 · see citing works
“A recent meta-analysis reported progression-free and overall survival were negatively impacted by antibiotic use [9], suggesting that disruption of the gut microbiome’s natural, eubiotic state by antibiotics dampens anti-cancer immunity, subsequently leading to poorer clinical outcomes [10].”
BackgroundMicrobiome modulates immunotherapy response in cutaneous squamous cell carcinoma
Voigt, A. Y., Walter, A., Young, T. H., Graham, J. P., Bittencourt, B. M. B., Pulido, Á. D. M., Prieto, K., Tsai, K. Y., Sundberg, J. P., & Oh, J. (2023) · Experimental Dermatology · doi:10.1111/exd.14864 · Cited by 13 · see citing works
“…treatments due to their pro-apoptotic, anti-proliferative and anti- epithelial- mesenchymal-transition capabilities (reviewed in, 33 e.g. for beta-lactam antibiotics, 34,35 ) while increasingly detrimental effects on immunotherapy patient outcomes have been described (e.g. 6,7,33,36,37 ).”
Chen, H., Han, K., He, Z., & Huang, Y. (2021) · Technology in Cancer Research & Treatment · doi:10.1177/15330338211033498 · Cited by 13 · see citing works
Baldessari, C., Pecchi, A., Marcheselli, R., Guaitoli, G., Bonacini, R., Valoriani, F., Torricelli, P., Reverberi, L., Menozzi, R., Pugliese, G., et al. (2021) · Immunotherapy · doi:10.2217/imt-2021-0038 · Cited by 13 · see citing works
Amadei, S. S., & Notario, V. (2020) · Antibiotics · doi:10.3390/antibiotics9090580 · Cited by 12 · see citing works
Santamaria, F., Roberto, M., Buccilli, D., Civita, M. A. D., Giancontieri, P., Maltese, G., Nicolella, F., Torchia, A., Scagnoli, S., Pisegna, S., et al. (2024) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2024.104405 · Cited by 11 · see citing works
Rühle, A., Zou, J., Glaser, M., Halle, L., Gkika, E., Schäfer, H. S., Knopf, A., Becker, C., Grosu, A., Popp, I., et al. (2023) · European Archives of Oto-Rhino-Laryngology · doi:10.1007/s00405-023-07868-3 · Cited by 11 · see citing works
“In a recent meta-analysis, the negative prognostic effect of antibiotics in cancer patients receiving immune checkpoint inhibitors was present independently of the time of antibiotic administration in relation to immune checkpoint inhibitor treatment [19].”
BackgroundFunayama, E., Hosonuma, M., Tajima, K., Isobe, J., Baba, Y., Murayama, M., Narikawa, Y., Toyoda, H., Tsurui, T., Maruyama, Y., et al. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117749 · Cited by 9 · see citing works
Dayhimi, A., Jazi, K., Bigdeli, Y., Farhoudi, F., Erfanimanesh, M., Esmaeili, M., Gorjipour, F., Ajami, M., & Pazoki–Toroudi, H. (2025) · Technology in Cancer Research & Treatment · doi:10.1177/15330338251365700 · Cited by 11 · see citing works
Li, C., Rich, B. E., Bullock, J. M., Barrière, O., Marier, J., & Beelen, A. P. (2022) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.15549 · Cited by 9 · see citing works
“Administering broad-spectrum antibiotics to patients with neutropenic infections can alter the gut microbiota, an important regulator of the systemic immune system, which may additionally interfere with antitumour immune responses.(12) Trilaciclib (COSELATM; G1 Therapeutics, Inc.”
BackgroundCruellas, M., Yubero, A., Zapata, M., Galvez, E. M., Ruiz, M. G., Isla, D., Lastra, R., Martínez‐Lostao, L., Ocariz, M., Pardo, J., et al. (2021) · Infection and Immunity · doi:10.1128/iai.00665-20 · Cited by 9 · see citing works
Topical antibiotics limit depigmentation in a mouse model of vitiligo
Touni, A. A., Sohn, R., Cosgrove, C., Shivde, R. S., Dellacecca, E. R., Abdel-Aziz, R. T. A., Cedercreutz, K., Green, S. J., Abdel‐Wahab, H., & Poole, I. C. L. (2024) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.13164 · Cited by 8 · see citing works
“Finally, a recent meta-analysis demonstrated a negative association between antibiotic use and the response to immune checkpoint blockade therapy in various types of cancers (Huang et al., 2019 ).”
Immune Checkpoint Inhibitors in Malignant Melanoma: Anti-PD-1, Anti-CTLA-4 and Anti-LAG-3 Therapies
Allen-Tejerina, A. M., Giannakis, P., Yau, T., Hillyar, C., & Rallis, K. S. (2026) · Current Oncology Reports · doi:10.1007/s11912-026-01750-1 · Cited by 7 · see citing works
“Similarly, antibiotics that alter the commensal gut flora decrease ICI efficacy across several cancer types [153, 154].”
Wu, Q., Zhang, S., Hua, X., Yu, H., & Zhong, Y. (2020) · Annals of Palliative Medicine · doi:10.21037/apm-20-1485 · Cited by 7 · see citing works
“Indeed, there were a few studies showing previous use of antibiotics might dampen the effect of immunotherapy (5-8).”
BackgroundHilakivi-Clarke, L. A., Verma, V., McDermott, M., Koak, P., & Andrade, F. D. O. (2022) · Frontiers in Microbiomes · doi:10.3389/frmbi.2022.1049688 · Cited by 7 · see citing works
“, 2021), and (ii) antibiotics that induce gut dysbiosis and eliminate critical commensal bacteria impair the effectiveness of ICBs (Huang et al., 2019; Yu et al., 2021; TsikalaVafea et al., 2021).”
BackgroundChen, J., Chen, S., Luo, H., Long, S., Yang, X., He, W., Wu, W., & Wang, S. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110919 · Cited by 7 · see citing works
Bonnefin, C., Schneider, S., Gerard, É., Dutriaux, C., Ferté, T., Prey, S., Guicheney, M., Ducharme, O., Pédeboscq, S., Beylot-Barry, M., et al. (2025) · European Journal of Cancer · doi:10.1016/j.ejca.2025.115223 · Cited by 6 · see citing works
Park, Y., Kang, D. H., & Chung, C. (2025) · Lung Cancer · doi:10.1016/j.lungcan.2025.108726 · Cited by 6 · see citing works
Deng, J., Kuang, W., Chen, W., Zhou, E., Wu, Y., Yang, Z., Chen, J., Cao, X., Yin, Z., Liu, J., et al. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.12.014 · Cited by 6 · see citing works
“Emerging evidence suggests that bacteria within the tumour-associated microbiota play pivotal roles in cancer development 64 , metastasis 5 — 7 , immunosurveillance 8,65,66 and chemoresistance 9,10 .”
Haight, P. J., Kistenfeger, Q., Riedinger, C. J., Khadraoui, W. K., Backes, F. J., Bixel, K. L., Copeland, L. J., Cohn, D. E., Cosgrove, C. M., O’Malley, D. M., et al. (2023) · Gynecologic Oncology · doi:10.1016/j.ygyno.2023.09.005 · Cited by 6 · see citing works
Mirabile, A., Rivoltini, L., Daveri, E., Vernieri, C., Mele, R., Porcu, L., Lazzari, C., Bulotta, A., Viganò, M. G., Cascinu, S., et al. (2020) · Cancers · doi:10.3390/cancers12051153 · Cited by 5 · see citing works
“Moreover, the use of antibiotics during immunotherapy in cancer patients has been associated with a lower PFS and OS [29,36,146].”
BackgroundAntibiotics and Immunotherapy: Too Much of Anything is Bad!
Gopalakrishnan, V., Sellman, B. R., Cohen, T. S., & Dennis, P. A. (2020) · European Urology · doi:10.1016/j.eururo.2020.07.027 · Cited by 5 · see citing works
- Authors
- Huang, X.-Z., Gao, P., Song, Y.-X., Xu, Y., Sun, J.-X., Chen, X.-W., Zhao, J.-H., & Wang, Z.-N.
- Affiliations
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University
- First Hospital of China Medical University (CN)
- Corresponding author
- Wang, Zhen-Ning
- ORCID
- Gao, Peng
- Venue
- OncoImmunology
- Publisher
- Informa UK Limited
- Published
- 2019-09-23
- Volume
- 8
- Issue
- 12
- Pages
- e1665973-e1665973
- ISSN
- 2162-4011 (ISSN-L)
- 2162-402X
- PMC
- PMC6844307
- OpenAlex
- W2976586374
- Cited by
- 132
- References
- 46
- Citations by year
- 2026: 14 · 2025: 14 · 2024: 9 · 2023: 24 · 2022: 24 · 2021: 22 · 2020: 23 · 2019: 1 · 2014: 1
- FWCI
- 7.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- OncoImmunology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- China Medical University
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Antibiotic Use and Resistance
- Keywords
- antibiotic use, immune checkpoint inhibitors, gut microbiota, cancer immunotherapy, overall survival, progression-free survival, antitumor immunity
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