Rational Immune Checkpoint Inhibitor-Based Combination Immunotherapy in Cancer: Mechanistic Design, Biomarker Selection, and Implications for Oncology Pharmacy.

Cancer immunotherapy has reshaped oncology, yet durable benefit remains limited for many patients because antitumor responses are constrained by multiple biological and clinical barriers. A targeted narrative review was conducted using peer-reviewed literature indexed in PubMed, Scopus, and Web of Science from January 2020 to April 2026, with additional landmark studies from earlier years included for essential mechanistic context. Priority was given to clinical, translational, and high-impact review articles examining combination strategies built on immune checkpoint blockade and related immune platforms. The evidence was synthesized by the main barriers each strategy aims to overcome, including poor immune priming, immune exclusion, immunosuppressive tumor microenvironments, adaptive resistance, and limited treatment durability. Across recent studies, combination immunotherapy is increasingly moving away from empiric regimen construction toward biologically rational approaches that integrate checkpoint blockade with chemotherapy, radiotherapy, antiangiogenic therapy, targeted agents, antibody-drug conjugates, bispecific antibodies, vaccines, and cellular platforms. Increasing emphasis has also been placed on integrated biomarkers that combine tumor-intrinsic, immune, spatial, and dynamic features to improve patient selection. At the same time, growing regimen complexity continues to raise challenges related to overlapping toxicity, sequencing, polypharmacy, and multidisciplinary implementation. Overall, the field is evolving toward mechanism-matched, biomarker-guided, and clinically manageable strategies that may broaden and refine the benefit of cancer immunotherapy.