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Published on: March 7, 2025

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

Ehsan Lotfi1,2, Fereshteh Golab1

  • 1Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.

Cancer Investigation
|August 28, 2026
PubMed

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.

Keywords:
BiomarkersCombination immunotherapyImmune checkpoint inhibitorsMicrobiomeTumor microenvironment

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