IMMUNOTHERAPY RESPONSE AND RESISTANCE MECHANISMS IN THE MICROBIOTA-IMMUNE AXIS

The shift from classical cytotoxic chemotherapy to immunotherapy, particularly immune check-point inhibitors (ICIs), in cancer treatment has led to a paradigm shift in the management of many solid tumors. Although blockade of programmed cell death-1 (PD-1), PD-ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4) has resulted in dramatic improvements in survival rates, primary and acquired resistance observed in a significant proportion of patients limits the clinical success of treatment. The inadequacy of traditional biomarkers such as tumor mutation burden and PD-L1 expression in explaining this heterogeneity of resistance has focused research on host factors, particularly the "microbiota–immune axis." This section analyzes the decisive role of the gastrointestinal microbiota in shaping the response to ICIs and modulating resistance mechanisms at the molecular and clinical levels. The interaction between the microbiota and the immune system occurs through molecular mimicry between microbial antigens and tumor neoantigens, immunometabolic programming mediated by short-chain fatty acids such as butyrate and secondary bile acids, and signaling pathways that regulate systemic inflammatory tone. These molecular messages determine the immunological character of the tumor microenvironment across a broad spectrum, from T cell priming to antigen presentation, modulating the elimination, equilibrium, and escape phases of cancer immune surveillance. Clinical data show that high microbial diversity and abundance of beneficial commensal taxa such as Akkermansia, Bifidobacterium, and Faecalibacterium increase treatment success; while dysbiosis developed due to broad-spectrum antibiotic use or poor nutrition weakens anti-tumor immunity and facilitates the development of resistance. Furthermore, current examples support that intratumoral bacteria contribute to local drug inactivation and immune escape. Innovative strategies such as fecal microbiota transplantation (FMT), personalized next-generation probiotics, and engineered therapeutic microbes are emerging to overcome current resistance mechanisms. The integration of microbiota-based data with multi-omic approaches enables the development of powerful biomarkers that can predict treatment response and toxicity. In oncology practice, obtaining a "microbiota history" prior to immunotherapy, rational antibiotic use, and avoiding unnecessary proton pump inhibitor (PPI) consumption are fundamental recommendations that optimize clinical success. In conclusion, the integration of microbiota modulation into standard treatment algorithms within the framework of precision medicine, while considering ethical and regulatory dimensions, will be an integral component of future immuno-oncology applications.