From microbes to molecules: Gut microbiota as a prerequisite threshold determinant for cancer immunotherapy efficacy

Cancer immunotherapy, represented by immune checkpoint inhibitors, adoptive cell therapy, and cancer vaccines, has revolutionized the clinical management of multiple malignant tumors, yet profound interindividual heterogeneity in treatment response and widespread primary/acquired resistance remain the most critical bottlenecks restricting its long-term clinical benefits. Accumulating preclinical and clinical evidence has unequivocally established the gut microbiota as a pivotal regulator of host anti-tumor immune responses. However, the vast majority of existing studies and reviews frame the gut microbiota as a mere adjuvant enhancer of immunotherapy efficacy, focusing solely on its role in boosting the upper limit of treatment effects, while neglecting its more fundamental role as a prerequisite for establishing a responsive immune baseline. In this review, we propose a unifying, evidence-based original core hypothesis: the gut microbiota is not merely an enhancer of cancer immunotherapy efficacy, but an indispensable prerequisite condition that sets the minimal baseline threshold for therapeutic responsiveness-a central thesis that distinguishes this review from previous descriptive work. Guided by this hypothesis, we systematically dissect the taxonomic and functional characteristics of threshold-determining gut microbiota, and clarify that microbial metabolites (e.g., short-chain fatty acids, bile acids, tryptophan derivatives) act as core molecular mediators translating microbial signals into host immune activation, which is critical for establishing the baseline efficacy threshold required for effective immunotherapy. We further perform a critical synthesis of clinical data from prospective cohorts, randomized controlled trials, and microbiota intervention studies, validating that threshold-based microbial signatures serve as non-invasive predictive biomarkers for immunotherapy outcomes, and propose mechanism-driven translational strategies targeting the gut microbiota (e.g., fecal microbiota transplantation, probiotic supplementation, dietary modulation) to reset the impaired immunotherapy efficacy threshold. This review provides a novel theoretical framework for understanding the microbiota-immunotherapy axis, which not only deepens the mechanistic insight into microbial metabolite-mediated immune regulation, but also facilitates the development of microbiota-guided personalized cancer immunotherapy and the overcoming of primary treatment resistance.