The advent of immune checkpoint inhibitors (ICIs) represents one of the most significant paradigm shifts in modern oncology, moving the therapeutic focus from the tumor cell to the host's immune system. By targeting critical negative regulatory pathways, primarily the Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4) and Programmed cell Death protein 1 (PD-1)/PD-L1 axes, these therapies have fundamentally altered the treatment landscape for a growing list of malignancies. This review provides a detailed exposition of the discrete molecular and cellular mechanisms underpinning CTLA-4 and PD-1 blockade, highlighting their distinct roles in the cancer-immunity cycle. We then delve deeply into the multifaceted and evolving landscape of therapeutic resistance, dissecting the tumor-intrinsic and extrinsic factors that lead to primary (de novo) or acquired (adaptive) non-response. Finally, we systematically analyze the scientific rationale and clinical evidence for current and emerging combination strategies. These approaches, including pairings with chemotherapy, radiotherapy, targeted agents, anti-angiogenics, and other immunotherapies, are being rationally designed to overcome specific resistance mechanisms, amplify therapeutic efficacy, and ultimately broaden the patient population who may achieve durable benefit from immunotherapy.
Shah et al. (Wed,) studied this question.
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