细胞外酸化抑制 METTL3-m(6)A-整合素β1 轴，从而损害 T 细胞浸润和抗肿瘤活性

The acidic metabolic byproducts within the tumor microenvironment (TME) hinder T cell effector functions.

However, their effects on T cell infiltration remain largely unexplored. Leveraging the comprehensive The Cancer Genome Atlas dataset, we pinpoint 16 genes that correlate with extracellular acidification and establish a metric known as the "tumor acidity (TuAci) score" for individual patients.

We consistently observe a negative association between the TuAci score and T lymphocyte score (T score) across various human cancer types.

Mechanistically, extracellular acidification significantly impedes T cell motility by suppressing podosome formation. This phenomenon can be attributed to the reduced expression of methyltransferase-like 3 (METTL3) and the modification of RNA N 6 -methyladenosine (m 6 A), resulting in a subsequent decrease in the expression of integrin 1 (ITGB1).

Importantly, enforced ITGB1 expression leads to enhanced T cell infiltration and improved antitumor activity.

Our study suggests that modulating METTL3 activity or boosting ITGB1 expression could augment T cell infiltration within the acidic TME, thereby improving the efficacy of cell therapy.