<p>Initially recognized for its role in digestion, the gut microbiota is now acknowledged as a critical regulator of the host immune system. It influences not only the initiation and progression of cancer but also key therapeutic mechanisms through metabolic reprogramming, production of virulence factors, and remodeling of the immune microenvironment. Despite significant advancements in patient outcomes attributed to novel multi-target inhibitors and immune checkpoint blockers, several clinical challenges persist, including therapy resistance, low response rates, and considerable toxicity. The increasing recognition of the role of microbiota in oncology has positioned its modulation as a pivotal strategy influencing the efficacy and overall success of treatment. This review summarizes how alterations in the gut microbiota influence tumorigenesis, shape immune responses, and mediate resistance to cancer therapies. This study also explores therapeutic strategies designed to modulate the microbiota by restoring ecological balance, enhancing anti-cancer immunity, or rectifying metabolic dysregulation to overcome therapy resistance and improve clinical outcomes. These approaches present a novel paradigm for addressing the challenge of drug resistance in cancer therapy.</p>