For years, the spotlight in immunotherapy has focused on T cells, immune checkpoints, and tumor genomic profiles. However, a new player has emerged on the oncology stage: the gut microbiome. This dynamic ecosystem of bacteria, viruses, and fungi that inhabits our intestines is no longer seen as a secondary actor in digestion, but as a fundamental modulator of the immune system, with direct implications for the response to cancer treatments.
Elkrief et al. (2025), in their publication in Annals of Oncology, provide a solid overview of how the composition of the gut microbiome can decisively influence the effectiveness of immune checkpoint inhibitors (ICI), a central class of drugs in immuno-oncology. The article offers a practical guide for clinical oncologists, based on preclinical and clinical evidence accumulated over the last decade.
Among the most relevant technical findings is the role of species such as Akkermansia muciniphila, Bifidobacterium longum, and Faecalibacterium prausnitzii, whose presence has been correlated with greater infiltration of CD8⁺ T cells and improved antitumor responses. At the molecular level, these bacteria appear to enhance type I interferon signaling, increase the expression of genes associated with immune activation, and influence the production of short-chain fatty acids (SCFAs), which modulate systemic inflammation and intestinal barrier integrity.
The authors also discuss how specific microbial signatures, identified through next-generation metagenomic sequencing (NGS), could be used as predictive biomarkers of response. In murine models, transplanting microbiota from responding patients into tumor-bearing mice restored the efficacy of ICIs, demonstrating that not only the immune system, but also the “intestinal content,” can transfer therapeutic sensitivity.
The article also highlights a clinically overlooked factor: the negative impact of antibiotic use on immunotherapy. Various studies have shown that recent use of antibiotics—particularly in the weeks before or after starting immunotherapy—is significantly associated with reduced ICI efficacy. This has been observed in multiple cancer types, including melanoma, non-small cell lung cancer (NSCLC), and renal carcinoma.
The mechanisms are diverse: antibiotics can drastically reduce microbiome diversity, eliminate key beneficial bacteria, and promote the expansion of opportunistic species with immunosuppressive activity. In patients recently exposed to antibiotics, lower objective response rates (ORR), shorter progression-free survival (PFS), and even reduced overall survival (OS) have been reported.
Elkrief and colleagues cite a meta-analysis showing that antibiotic use within 60 days of starting ICI treatment is consistently associated with poorer clinical outcomes. This has prompted many cancer centers to reconsider the empirical use of antibiotics in immunotherapy candidates, favoring more precise decisions based on cultures and infectious biomarkers.
A particularly relevant aspect of the article is its detailed analysis of fecal microbiota transplantation (FMT). This procedure, which involves transferring fecal material from a healthy donor to a recipient, has emerged as a promising strategy to reverse resistance to immunotherapy. The clinical trials mentioned by Elkrief and his team—such as those conducted by Baruch et al. and Davar et al.—show that FMT can restore ICI sensitivity in patients with metastatic melanoma who had previously not responded to treatment.
Figure 1. Gut microbiota modulates antitumor immunity via Type I IFN signaling.
Beneficial bacteria promote IFN-I production, enhancing inflammation, CD8⁺ T cell activation, and tumor infiltration. Antibiotic-induced dysbiosis impairs this pathway, while FMT can help restore immune function.
In these studies, patients received FMT from donors who had achieved durable clinical responses to ICIs. Subsequently, recipients showed favorable changes in their gut microbiome, activation of specific immune pathways, and, most importantly, tumor regression in some cases. The authors emphasize that although this intervention is still experimental, it holds therapeutic potential and opens the door to designing personalized bacterial consortia, without the need to use whole fecal samples.
Despite its promise, FMT faces logistical, regulatory, and scientific challenges: from donor standardization, microbial consortia characterization, to long-term safety in immunocompromised populations. For this reason, Elkrief et al. suggest that the future may lie more in “targeted microbiotherapy”—precision probiotics, modulating diets, or specifically cultured bacteria—than in full transplantation.
In practical terms, the authors conclude that the microbiome could become a new dimension of personalized medicine. Evaluating a patient’s microbial profile before initiating immunotherapy could become as important as analyzing the tumor’s mutational landscape. If the clinical impact of certain bacteria can be validated, we may be facing a new generation of biomarkers and adjunct therapies based on microbial manipulation.
The implication is clear: ignoring the microbiome in the era of immuno-oncology is to overlook a critical piece of the therapeutic puzzle. Its modulation can not only improve response rates but also prevent toxicities, enhance treatment tolerance, and open new therapeutic windows for patients previously considered non-responders. The oncology of the future will be both genomic and ecological, and the gut—this often-forgotten organ—may hold the key to unlocking the full potential of immunotherapy.
Main Reference:
Arielle Elkrief et al. Gut Microbiota in Immuno-Oncology: A Practical Guide for Medical Oncologists With a Focus on Antibiotics Stewardship. Am Soc Clin Oncol Educ Book 45, e472902(2025). https://ascopubs.org/doi/10.1200/EDBK-25-472902
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