# A comprehensive review of mechanisms underlying resistance to immune checkpoint inhibitors

## TL;DR

This review explores why some cancer patients don't respond to immune checkpoint inhibitors and how to improve treatment strategies.

## Contribution

The paper provides an integrative overview of molecular and cellular mechanisms behind resistance to immune checkpoint inhibitors.

## Key findings

- Primary and acquired resistance to ICIs involve distinct biological mechanisms.
- Key factors include antigen presentation, interferon signaling, and immune exclusion in the tumor microenvironment.
- Emerging biomarkers may help personalize immunotherapy and improve patient outcomes.

## Abstract

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 tumour-intrinsic and tumour-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 tumour 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.