The influence of fatty acid metabolism on T cell function in lung cancer

Abstract

The tumor microenvironment (TME) is a complex ecosystem, encompassing a variety of cellular and non-cellular elements surrounding and interacting with cancer cells, overall promoting tumor growth, immune evasion, and therapy resistance. In the context of solid tumors, factors, such as hypoxia, nutritional competition, increased stress responses, glucose demand, and PD-1 signals strongly influence metabolic alterations in the TME, highly contributing to the maintenance of a tumor-supportive and immune-suppressive milieu. Cancer cell-induced metabolic alterations partly result in an increased fatty acid (FA) metabolism within the TME, which strongly favors the recruitment of immune-suppressive M2 macrophages and myeloid-derived suppressor cells, crucial contributors to T-cell exhaustion, tumor exclusion, and decreased effector functions. The drastic pro-tumoral changes induced by the tumor metabolic rewiring result in signaling loops that support tumor progression and metastatic spreading, and negatively impact therapy efficacy. As tumor- and immune metabolism are increasingly gaining attention due to their potential therapeutic implications, we discuss the effects of altered lipid metabolism on tumor progression, immune response, and therapeutic efficacy in the context of lung cancer. In particular, we focus our analysis on the tumor-induced metabolic alterations experienced by T lymphocytes and the possible strategies to overcome immunotherapy resistance by targeting specific metabolic pathways in T cells.