Fig. 3 |. autophagy in immune cells in the tumour microenvironment.

a | In the tumour microenvironment (TME), T cells rely on autophagy to support their survival and differentiation. Basal levels of autophagy in naive T cells maintain their quiescence and protect them from mitochondria-derived reactive oxygen species (ROS)-induced apoptosis. High levels of lactate in tumours disrupt autophagy of naive T cells and impair the antitumour response in mouse models. High levels of potassium or low levels of nutrients in the TME constrain the nutrient uptake in effector T cells and cause functional caloric restriction, which induces autophagy through mTOR complex 1 (mTORC1) inhibition. Autophagy is critical for mitochondrial integrity, which determines effector T cell differentiation via metabolic reprogramming. High levels of arginase 2 (ARG2) expression in tumour-infiltrating regulatory T cells (T_reg cells) may maintain their high level of autophagy. The loss of autophagy in T_reg cells switches their metabolism from oxidative phosphorylation (OXPHOS) to glycolysis with active mTORC1 and MYC, which leads to FOXP3 instability. Increased apoptosis and defective function in autophagy-deficient T_reg cells contribute to greater tumour resistance. b | Tumour-associated macrophages (TAMs) take advantage of lipidate microtubule-associated protein 1A/1B light chain 3 (LC3)-associated phagocytosis (LAP) to degrade apoptotic cancer cells. LAP deficiency in TAMs leads to the release of mitochondrial DNA from apoptotic cancer cells, which induces type I interferon response through the cGAS–stimulator of interferon genes (STING) pathway and antitumour activity. c | In ovarian cancer metastasis, TIM4⁺ TAMs are embryonically originated and locally sustained, whereas TIM4⁻ TAMs are replenished from circulating monocytes. Relative to TIM4⁻ TAMs, TIM4⁺ TAMs manifest high levels of oxidative phosphorylation and adapt mitophagy to alleviate oxidative stress. High levels of ARG1 in TIM4⁺ TAMs contribute to potent mitophagy activities via weakened mTORC1 activation due to low arginine levels resulting from ARG1-mediated metabolism. Furthermore, genetic deficiency of autophagy element FAK family interacting protein of 200 kDa (FIP200) results in TIM4⁺ TAM loss via ROS-mediated apoptosis, and elevated T cell immunity and tumour inhibition in vivo. ATG13, autophagy-related protein 13; BCL2, B cell lymphoma 2; MCT1, monocarboxylate transporter 1; TIM4, T cell immunoglobulin and mucin domain-containing molecule 4; ULK1, unc-51-like kinase 1.