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Wu et al. identifies a novel mechanism by which the tumor glycolysis pathway inhibits T cell-mediated killing through TNF-α signaling, providing new insights for enhancing anti-tumor immunity. The authors utilized genome-wide CRISPR screening in murine tumor cells co-cultured with cytotoxic T cells (CTLs) to identify the mechanisms of resistance to CTL-mediated killing. The study found that the inactivation of Glut1, a glucose transporter predominantly expressed in tumor cells, significantly sensitized tumor cells to CTL-mediated killing. It is demonstrated that inhibition of Glut1 led to increased levels of reactive oxygen species (ROS), which in turn sensitized tumor cells to TNF-α-induced cell death through downregulation of c-FLIP, a critical negative regulator of TNF-α-induced cell death. Furthermore, Glut1 inhibition synergized with anti-PD-1 therapy in mouse models, suggesting its potential as a novel immunotherapy target.

The study also revealed a striking difference in the expression patterns of glucose transporters in tumor and immune cells. Glut1 was highly expressed in tumor cells, while GLUT3, a high-affinity glucose transporter, was predominantly expressed in immune cells. This differential expression provides a rationale for targeting Glut1 in cancer immunotherapy.

Furthermore, the study demonstrated that Glut1 KO tumors were more sensitive to immune-mediated elimination through the TNF-a pathway in vivo. In addition, Glut1 inhibition potentiated anti-tumor immunity in vivo, leading to increased infiltration of immune cells, including T cells and natural killer (NK) cells.

Clinical relevance of targeting the glycolysis pathway was also demonstrated. The study found a negative correlation between the glycolysis pathway level and CD8+ T cell infiltration in bulk tumors. Moreover, patients with low glycolysis signature or GLUT1 expression level and high TNF-α expression level showed better survival outcomes.

In summary, this study provides compelling evidence that the tumor glycolysis pathway plays a crucial role in conferring resistance to T cell-mediated killing. Inhibition of Glut1 sensitizes tumor cells to TNF-a-induced cell death, leading to enhanced anti-tumor immunity. These findings suggest that targeting Glut1 may represent a novel strategy to boost anti-tumor immunity in cancer immunotherapy.

In addition to inhibition of glycolysis in tumor cells , reprogramming of other metabolic activities in the tumor microenvironment may also be associated with pro-inflammatory and anti-tumor effects. Tumor-associated macrophages (TAMs) are a subset of macrophages that accumulate in the tumor microenvironment and play a pivotal role in cancer progression. Traditionally, TAMs are known to support tumor growth through various mechanisms, such as promoting angiogenesis, supporting tumor cell proliferation, and suppressing antitumor immunity. However, the study by Liu et al. challenges the conventional view of TAMs by uncovering their potential anti-tumorigenic functions. The authors demonstrate that agonistic anti-CD40 monoclonal antibodies can reeducate TAMs towards an anti-tumorigenic phenotype, leading to tumor growth suppression and enhancing antitumor responses through epigenetic reprogramming of pro-inflammatory genes.

Notably, metabolic reprogramming involving the activation of fatty acid oxidation (FAO) and glutamine metabolism, plays an indispensable role in the phenotype-switching of TAMs mediated by CD40 signaling. Specifically, FAO generates acetyl-CoA, which is then used by CD40 signaling to increase histone acetylation at the promoters and enhancers of pro-inflammatory genes, thereby activating them. Furthermore, CD40 signaling also triggers glutamine to lactate conversion, which  is carried out through the coordinated activity of cytosolic enzymes, including ACLY, MDH1, and ME1. The reprogramming of glutamine metabolism is essential for CD40-induced NAD⁺/NADH ratio regulation, OXPHOS, and pro-inflammatory polarization.

The mechanism of pro-inflammatory activation via CD40 signaling is distinct from the typical metabolic changes induced by lipopolysaccharide, which usually leads to aerobic glycolysis and breaks the tricarboxylic acid cycle. In addition, this study challenges the traditional view of TAMs as solely pro-tumorigenic and reveals their potential to acquire anti-tumorigenic functions through metabolic reprogramming induced by CD40 signaling. These findings provide new insights into the multifaceted roles of TAMs in cancer and suggest that targeting metabolic pathways could be a promising strategy to reeducate TAMs for cancer immunotherapy.

1. Wu L, Jin Y, Zhao X, Tang K, Zhao Y, Tong L, Yu X, Xiong K, Luo C, Zhu J, Wang F, Zeng Z, Pan D. Tumor aerobic glycolysis confers immune evasion through modulating sensitivity to T cell-mediated bystander killing via TNF-α. Cell Metab. 2023 Sep 5;35(9):1580-1596.e9.

2. Liu PS, Chen YT, Li X, Hsueh PC, Tzeng SF, Chen H, Shi PZ, Xie X, Parik S, Planque M, Fendt SM, Ho PC. CD40 signal rewires fatty acid and glutamine metabolism for stimulating macrophage anti-tumorigenic functions. Nat Immunol. 2023 Mar;24(3):452-462.