Abstract
Resistance to immune checkpoint inhibitors (ICIs) represents a major challenge for the effective treatment of non-small cell lung cancer (NSCLC). Tumor heterogeneity has been identified as an important mechanism of treatment resistance in cancer and has been increasingly implicated in ICI resistance. The diversity and clonality of tumor neoantigens, which represent the target epitopes for tumor-specific immune cells, have been shown to impact the efficacy of immunotherapy. Advances in genomic techniques have further enhanced our understanding of clonal landscapes within NSCLC and their evolution in response to therapy. In this review, we examine the role of tumor heterogeneity during immune surveillance in NSCLC and highlight its spatial and temporal evolution as revealed by modern technologies. We explore additional sources of heterogeneity, including epigenetic and metabolic factors, that have come under greater scrutiny as potential mediators of the immune response. We finally discuss the implications of tumor heterogeneity on the efficacy of ICIs and highlight potential strategies for overcoming therapeutic resistance.