Subtype-Agnostic Biomarkers of Immunotherapy Response in Lung Cancer

Abstract Immunotherapy has transformed the lung cancer treatment landscape, establishing a role in nearly all histologic subtypes, including non–small cell and small cell lung cancers. However, only a few biomarkers, including PD-L1 tumor proportion score, tumor mutational burden, and microsatellite instability, are currently available, and their predictive value remains inconsistent across different histologies. The biological heterogeneity of lung tumors and the dynamic interplay between systemic therapies and the tumor microenvironment (TME) further complicate biomarker development. At the same time, novel immunotherapeutic strategies, including bispecific antibodies and antibody–drug conjugates, are expanding the spectrum of immune targets beyond conventional checkpoint inhibition, highlighting the need for biomarkers that better reflect the functional state of the TME. In this review, we address the limitations of currently used biomarkers across lung cancer histologies and describe emerging immune-related biomarkers encompassing innate immune infiltration, antigen presentation capacity, cytotoxic T-cell activation, and inflammatory signaling; these have shown promise as histology-independent predictors of response. Robust prospective studies are essential to validate integrated signatures capable of capturing profiles of patients who are most likely to respond to immune checkpoint inhibitors and next-generation treatments.