REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicCancer Immunotherapy and Tumor Escape Mechanisms: New Insights and Future DirectionsView all 5 articles
A Comprehensive Review of Mechanisms Underlying Resistance to Immune Checkpoint Inhibitors
Provisionally accepted
- 1Medical Oncology, Institut Paoli-Calmettes, Marseille, France
- 2Team immunity and cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Marseille, France
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Immune checkpoint inhibitors (ICIs) have revolutionized the management of multiple malignancies, offering durable clinical benefit in a subset of patients. However, the emergence of distinct response patterns has revealed two major challenges: primary resistance, observed in patients who fail to respond from the outset, and acquired resistance, which develops after an initial period of disease control. These two resistance phenotypes likely arise from divergent biological mechanisms, involving both tumor-intrinsic and tumor-extrinsic factors. A comprehensive understanding of these processes is essential to optimize therapeutic strategies, particularly through rational combinations of ICIs with novel immunomodulators, targeted therapies, or conventional treatments. In this review, we provide an integrative overview of the key molecular and cellular mechanisms underlying both primary and acquired resistance to ICIs, encompassing alterations in antigen presentation, interferon signalling, oncogenic and metabolic pathways, as well as immune exclusion within the tumor microenvironment. We also highlight emerging predictive biomarkers of response and resistance—ranging from genomic and transcriptomic signatures to soluble immune checkpoints and non-immune circulating markers— aimed at refining patient selection and guiding personalized immunotherapy. Ultimately, deciphering these mechanisms will be pivotal for designing the next generation of immune-based combinations to overcome therapeutic resistance and expand the population of patients who can benefit from immune checkpoint blockade.
Keywords: acquired resistance, Immunosuppression, Immunotherapy, neoantigen machinery defects, primary resistance, Tumormicroenvironment
Received: 30 Oct 2025; Accepted: 12 Feb 2026.
Copyright: © 2026 Bertucci, Taleb, Billon, Fernez and Rochigneux. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Alexandre Bertucci
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