全反式维甲酸与兰索拉唑增强 NKG2D-CAR-T 对乳腺癌的治疗作用

In solid cancer, the tumor microenvironment (TME) poses significant challenges to chimeric antigen receptor (CAR) T cell therapy due to its dense physical barrier, abnormal metabolism, and immunosuppressive factors.

This study addresses these limitations using a synergistic approach involving all-trans retinoic acid (ATRA) and lansoprazole (LPZ) to target fibrosis and acidity, respectively. In vitro, ATRA reversed activated cancer-associated fibroblasts to a quiescent state, reducing -SMA production, while LPZ increased tumor-site pH ( pH = 0.

54) by inhibiting V-ATPase expression. In a triple-negative breast cancer (TNBC) model, a temperature-sensitive hydrogel delivering ATRA and LPZ was administered prior to drug-loaded NKG2D-CAR T (N-CAR T) cell injection, achieving a tumor inhibition rate of 72. 08%.

Notably, co-culture with ATRA and LPZ enhanced N-CAR T activity, cytokine secretion, and promoted differentiation into more lethal CD8 + subtypes (p < 0. 0001), amplifying the immune response.

These findings establish a targeted, potent, and low-toxicity preconditioning strategy to enhance CAR T cell efficacy in solid tumors, supporting further validation in more complex models and human-relevant systems.