What is it about?

The mechanisms underlying acquired immunotherapy resistance (AIR) are less understood. In this study, we generated non–small cell lung cancer (NSCLC) mouse models of AIR and found that tumor cell-expressing collagens, which formed physical barriers against T cell infiltration and attack, were a major tumor cell–intrinsic mechanism contributing to AIR. Genetically or pharmaceutically targeting these barriers could resensitize tumors for immunotherapy.

Featured Image

Why is it important?

Immunotherapy has revolutionized oncology practice, yet the emergence of acquired resistance continues to pose a significant clinical challenge that substantially compromises patient outcomes. This study elucidates a novel resistance mechanism wherein tumor cells actively establish collagen-based physical barriers (COL3A1/COL6A1) as a sophisticated immune evasion strategy. Our findings shift the current paradigm from immune cell-centric explanations to a tumor cell-autonomous model of resistance mediated through microenvironmental remodeling. Importantly, we demonstrate that targeted disruption of these collagenous barriers represents a therapeutically actionable strategy to restore treatment sensitivity, thereby addressing a critical unmet need in cancer immunotherapy.

Perspectives

Physical barriers play critical roles in both physiological and pathological conditions. In this study, we propose that COL3A1 and COL6A1, expressed by tumor cells themselves, contribute to the castle-like and armor-like physical barriers, respectively, and provide acquired immunotherapy resistance.

Chong Chen
Sichuan University

Read the Original

This page is a summary of: Acquired resistance to immunotherapy by physical barriers with cancer cell–expressing collagens in non–small cell lung cancer, Proceedings of the National Academy of Sciences, June 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2500019122.
You can read the full text:

Read

Contributors

The following have contributed to this page