Commentary: understanding acquired resistance to immunotherapy in non-small cell lung cancer

Programmed cell death protein ligand 1 (PD-L1) blockade has emerged as a key therapy for advanced non-small cell lung cancer (NSCLC). Unfortunately, one of the key barriers in the treatment is the acquired resistance to PD-L1, even though after the initial response to the treatment, more than 60% of the patients develop acquired resistance. In a study published in the Cancer Cell journal by Memon et al. (2024), a cohort of 1,201 patients with NSCLC was analyzed to evaluate the relapse mechanism. They identified subtypes with persistent or upregulated interferon γ (IFNγ) signaling, immune dysfunction, and antigen presentation defects. Murine models exposed to chronic IFNγ recapitulated these features, highlighting that a chronically inflamed microenvironment drives resistance. These insights underscore the need for adaptive therapies that dynamically target evolving tumor-immune interactions.