Simple SummaryImmunotherapy for non-small cell lung cancer (NSCLC) is a clinical reality with impressive efficacy for some patients. However, less than half of them will benefit from this therapeutic regime, and finding indicators of response is necessary for selecting the patients likely to respond. So far, detection of PD-L1 in tumors by immunohistochemistry is the only validated predictive biomarker. In recent years, certain changes in the tumor cells (intrinsic alterations), including mutations, epigenetic changes and metabolic rewiring, have been shown to modify the type of tumor microenvironment (TME) where such a tumor grows. This TME may determine response or refractoriness to immunotherapy. Examples of key mutations areKRAS,SKT11(LKB1),KEAP1andTP53, as well as co-mutations of these genes. Reshaping the TME with novel strategies in these particular TMEs could increase the efficacy of immunotherapy in lung cancer patients.AbstractDespite the great clinical success of immunotherapy in lung cancer patients, only a small percentage of them (<40%) will benefit from this therapy alone or combined with other strategies. Cancer cell-intrinsic and cell-extrinsic mechanisms have been associated with a lack of response to immunotherapy. The present study is focused on cancer cell-intrinsic genetic, epigenetic, transcriptomic and metabolic alterations that reshape the tumor microenvironment (TME) and determine response or refractoriness to immune checkpoint inhibitors (ICIs). Mutations inKRAS,SKT11(LKB1),KEAP1andTP53and co-mutations of these genes are the main determinants of ICI response in non-small-cell lung cancer (NSCLC) patients. Recent insights into metabolic changes in cancer cells that impose restrictions on cytotoxic T cells and the efficacy of ICIs indicate that targeting such metabolic restrictions may favor therapeutic responses. Other emerging pathways for therapeutic interventions include epigenetic modulators and DNA damage repair (DDR) pathways, especially in small-cell lung cancer (SCLC). Therefore, the many potential pathways for enhancing the effect of ICIs suggest that, in a few years, we will have much more personalized medicine for lung cancer patients treated with immunotherapy. Such strategies could include vaccines and chimeric antigen receptor (CAR) cells.