Drug Resistance Mechanisms in Cancer Therapy

Therapeutic resistance remains a major impediment to durable clinical success in cancer treatment, affecting chemotherapy, targeted therapy, and immunotherapy alike. Despite initial responses, tumors frequently develop intrinsic or acquired resistance driven by genomic instability, intratumoral heterogeneity, signaling plasticity, and adaptive interactions with the tumor microenvironment. This chapter provides a comprehensive and mechanistic overview of the molecular and cellular processes that underlie resistance across diverse anticancer modalities. Resistance to targeted therapies is discussed within a convergence-based framework encompassing pathway reactivation, pathway bypass, and pathway indifference, highlighting genetic alterations, compensatory signaling, and phenotypic or lineage switching as key drivers of treatment failure. Classical mechanisms of chemotherapy resistance-including altered drug transport and efflux, reduced uptake, target modification, metabolic detoxification, enhanced DNA repair, and evasion of apoptosis-are examined in detail. The chapter further explores the contributions of epigenetic regulation, microRNA-mediated control, cancer stem cells, and tumor microenvironmental factors such as hypoxia, stromal signaling, extracellular acidosis, and exosome-mediated communication. Mechanisms of resistance to immunotherapy, involving both tumor-intrinsic immune evasion and tumor-extrinsic immunosuppressive networks, are also addressed. Finally, emerging strategies to overcome resistance—including rational combination therapies, adaptive treatment approaches, biomarker-guided precision medicine, nanotechnology-based drug delivery, synthetic lethality, and multi-omics and artificial intelligence-driven frameworks—are discussed. This chapter aims to provide an integrated and translational perspective to inform the development of more durable and effective cancer therapies.