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Malignant tumours remain a major global health challenge, necessitating integrated, multi‑modal treatment strategies. This review provides a critical synthesis of mechanism‑based therapeutic approaches, emphasising three cross‑cutting themes: (i) the clinical problem of primary and acquired resistance, (ii) the biological rationale for treatment sequencing and rational combinations, and (iii) patient‑centred toxicity management. Landmark trials and real‑world evidence are analysed alongside emerging data to illustrate how resistance mechanisms shape therapeutic decision‑making. Toxicity profiles and clinically relevant drug-drug interactions are systematically examined, with particular attention to patient‑reported outcomes as a means of balancing efficacy with tolerability. Special focus is given to the mechanistic basis of synergistic strategies-such as the immunogenic role of chemotherapy preceding checkpoint blockade-and to the translational potential of novel platforms including mRNA vaccines and proteolysis‑targeting chimeras (PROTACs). By integrating biological insight with clinical pragmatism, this review outlines current standards, persistent gaps, and future directions for optimising cancer therapy.