The role of the microbiota in cancer drug resistance and emerging therapeutic strategies.

Drug resistance remains a significant obstacle in cancer therapy, severely compromising therapeutic efficacy and patient survival outcomes. Targeted therapy is now a central strategy for cancers with defined molecular abnormalities, employing agents that interact with specific genetic or molecular targets. Immunotherapy has emerged as a transformative approach in oncology by enhancing the immune system's ability to identify and eradicate cancer cells. Although microbial communities are increasingly acknowledged for their involvement in tumorigenesis and metastasis, their impact on drug resistance, including resistance to chemotherapy, immunotherapy, and targeted therapy, remains insufficiently investigated. Clinical evidence further reveals significant correlations between microbiota composition and survival outcomes, such as progression-free survival and recurrence rates. Microbiota contribute to resistance through complex mechanisms. Pathogenic bacteria can impair chemotherapy by degrading drugs and suppressing immune responses, whereas certain beneficial bacteria may enhance immunity and modulate metabolism. Notably, intratumoral microbiota directly modulate chemoresistance development through localized actions within the tumor microenvironment. This review synthesizes clinical data and mechanistic studies to delineate microbial-drug interactions, emphasizing how pathogens drive resistance through multifactorial pathways while probiotics mitigate treatment toxicity and restore drug sensitivity. We further propose novel therapeutic strategies leveraging microbe-drug interplay to overcome resistance and alleviate chemotherapy side effects, offering new approaches to enhance the efficacy of immunotherapy and targeted therapy. These findings advance the understanding of microbial contributions to drug resistance and provide new directions for clinical application in precision cancer therapy.