[Resistance to immunotherapy in non-small cell lung cancer: State of the art]

Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality worldwide. Immunotherapy has significantly reshaped its treatment, leading to improved survival in a subset of patients. However, failed initial response or acquired resistance may limit the long-term benefits of immunotherapy.

Resistance to immunotherapy arises from complex and multifactorial mechanisms. They include intrinsic tumor cell alterations - such as STK11 and KEAP1 mutations, antigen presentation defects, and impaired IFNγ signaling - as well as extrinsic factors related to the tumor microenvironment, including hypoxia, immunosuppressive cell infiltration, and T-cell exclusion. In response, several combination strategies have been explored: immunotherapy with chemotherapy, anti-angiogenic agents, alternative immune checkpoint inhibitors (e.g., CTLA-4, TIGIT, LAG-3), or innate immune modulators (e.g., STING, RIG-I), with encouraging early results.

Despite recent progress, current approaches remain primarily focused on the tumor and its microenvironment, often overlooking host-related factors - such as age, comorbidities, dysbiosis, and chronic inflammation - that can significantly impact immune responsiveness. More refined patient stratification, incorporating tumor, immune, and host-derived immune and non-immune biomarkers, is essential to better tailor treatments and improve outcomes.

The future of immunotherapy in NSCLC will likely be premised on a holistic understanding of tumor biology, immune dynamics, and host characteristics. Such an integrated approach is key to overcoming current limitations, enabling personalized strategies, and broadening the clinical benefit of immunotherapy to a wider patient population.