Background:The gut microbiome plays a pivotal role in shaping systemic immunity and modulating anti-tumor responses. Preclinical and clinical studies have shown that higher gut microbial diversity and the presence of specific commensal taxa correlate with improved responses to immune checkpoint inhibitors (ICI) in melanoma. Conversely, broad-spectrum antibiotics can induce dysbiosis, reducing T cell activation and cytokine production, and have been linked to diminished ICI efficacy in several cancer types.Methods:We conducted a systematic review and meta-analysis of seven retrospective cohorts (total n = 5213) comparing overall survival in cutaneous melanoma (CM) patients who did or did not receive systemic antibiotics within six weeks before ICI initiation. From each study, we extracted hazard ratios (HRs) for death, antibiotic-to-ICI interval, ICI regimen (PD-1 monotherapy vs. PD-1 + CTLA-4 combination), cohort size, and country. Pooled log-HRs were estimated under fixed-effect and random-effects (REML) models. Statistical heterogeneity was quantified by Cochran’s Q and I2statistics, and τ2. We performed leave-one-out sensitivity analyses, generated a Baujat plot to identify influential studies, applied trim-and-fill to assess publication bias, and ran meta-regressions for regimen, antibiotic timing, sample size, and geography.Results:Under the fixed-effect model, antibiotic exposure corresponded to a pooled HR of 1.26 (95% CI 1.13–1.41;p< 0.001). The random-effects model yielded a pooled HR of 1.55 (95% CI 1.21–1.98;p= 0.0005) with substantial heterogeneity (Q = 25.1; I2= 76%). Prediction intervals (0.78–3.06) underscored between-study variability. Leave-one-out analyses produced HRs from 1.50 to 1.75, confirming robustness, and the Baujat plot highlighted two cohorts as primary heterogeneity drivers. Trim-and-fill adjusted the HR to 1.46 (95% CI 1.08–1.97). In subgroup analyses, combination therapy studies (k = 4) showed a pooled HR of ~1.9 (I2= 58%) versus ~1.3 (I2= 79%) for monotherapy. Meta-regression attributed the largest variance to the regimen (R2= 32%; β(monotherapy) = −0.35;p= 0.13).Conclusions:Pre-ICI antibiotic use in CM is consistently associated with a 26–55% increase in mortality risk, particularly with PD-1 + CTLA-4 combinations, reinforcing the mechanistic link between microbiome integrity and ICI success. Looking ahead, integrating prospective microbiome profiling into clinical trials will be critical to personalize ICI therapy, clarify causality, and identify microbial biomarkers for optimal treatment selection. Prospective, microbiome-integrated trials promise to refine melanoma immunotherapy by tailoring antibiotic stewardship and microbial interventions to enhance patient outcomes.
背景：肠道微生物组在塑造全身免疫及调节抗肿瘤反应中起关键作用。临床前及临床研究表明，较高的肠道微生物多样性和特定共生菌群的存在与黑色素瘤患者对免疫检查点抑制剂（ICI）的更好应答相关。相反，广谱抗生素可导致菌群失调，降低T细胞活化和细胞因子产生，并与多种癌症类型中ICI疗效减弱相关。 方法：我们对七个回顾性队列（总样本量n = 5213）进行了系统综述和荟萃分析，比较了皮肤黑色素瘤（CM）患者在开始ICI治疗前六周内是否接受全身性抗生素治疗的总生存期。从每项研究中提取了死亡风险比（HR）、抗生素使用与ICI启动的时间间隔、ICI治疗方案（PD-1单药治疗 vs. PD-1 + CTLA-4联合治疗）、队列规模及国家信息。在固定效应和随机效应（REML）模型下估计了合并对数风险比。通过Cochran's Q检验、I²统计量和τ²量化统计异质性。进行了留一法敏感性分析，绘制Baujat图以识别影响较大的研究，应用剪补法评估发表偏倚，并对治疗方案、抗生素使用时机、样本量和地域进行了荟萃回归分析。 结果：在固定效应模型下，抗生素暴露对应的合并HR为1.26（95% CI 1.13–1.41；p < 0.001）。随机效应模型得出的合并HR为1.55（95% CI 1.21–1.98；p = 0.0005），存在显著异质性（Q = 25.1；I² = 76%）。预测区间（0.78–3.06）强调了研究间的变异性。留一法分析得出的HR范围为1.50至1.75，证实了结果的稳健性；Baujat图显示两个队列是异质性的主要来源。剪补法调整后的HR为1.46（95% CI 1.08–1.97）。亚组分析显示，联合治疗研究（k = 4）的合并HR约为1.9（I² = 58%），而单药治疗研究约为1.3（I² = 79%）。荟萃回归分析表明治疗方案解释的变异最大（R² = 32%；β（单药治疗）= −0.35；p = 0.13）。 结论：在CM患者中，ICI治疗前使用抗生素与死亡风险增加26–55%持续相关，尤其在PD-1 + CTLA-4联合治疗方案中，这进一步证实了微生物组完整性与ICI疗效之间的机制联系。展望未来，将前瞻性微生物组分析整合到临床试验中，对于个体化ICI治疗、阐明因果关系以及识别微生物生物标志物以实现最佳治疗选择至关重要。前瞻性、整合微生物组分析的试验有望通过优化抗生素管理和微生物干预措施来改善黑色素瘤免疫治疗，从而提高患者预后。
肿瘤(癌症)患者之家