Mechanisms of Resistance to Immune Checkpoint Inhibitors and Therapeutic Strategies to Overcome Them: An Integrative Review.

Authors

Ehsan Lotfi, Fereshteh Golab

Published in

Cancer investigation. Pages 1-22. Aug 28, 2026. Epub Aug 28, 2026.

Abstract

Immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, CTLA-4, and LAG-3 have transformed cancer therapy, but resistance limits durable benefit. This integrative review summarizes primary, adaptive, and acquired resistance driven by tumor-intrinsic defects, suppressive tumor microenvironmental programs, and host-related factors. We discuss mechanism-based strategies to overcome resistance, including combination immunotherapy, antiangiogenic treatment, TGF-β targeting, myeloid reprogramming, epigenetic and metabolic interventions, microbiome modulation, and cellular or vaccine-based approaches. The findings support a precision immuno-oncology framework based on composite biomarkers, longitudinal monitoring, and adaptive treatment selection matched to dominant resistance mechanisms.

PMID:
42665439
Bibliographic data and abstract were imported from PubMed on 29 Aug 2026.

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