pH-neutralization strategy to suppress GPCR68 spatiotemporally activates T cells and enhances anti-tumor immunity.

Abstract

The acidic tumor microenvironment (TME) promotes immune escape by suppressing T-cell function, creating a major barrier to immunotherapy. Here, acidic pH-mediated impairment of T cell responses via the proton-sensing receptor GPCR68 is identified, whereas mild extracellular alkalinization counteracts this pathway to restore T cell effector function. GPCR68 acts as a negative regulator of T cell-driven anti-tumor immunity, as evidenced by the enhanced cytokine production (IFN-γ, TNF-α) and suppressed tumor growth in T cell-specific GPCR68 knockout mice (GPCR68^fl/flCD4^Cre). Thus, a borate-optimized local tumor therapy (BOLT) strategy is engineered to target GPCR68, based on alkali-metal-ion-modulated borate bioactive glass, which is integrated, spatiotemporally multiple responsive, and locally injectable. BOLT combats tumors dually by potentiating T cell immunity and inducing tumor ferroptosis. It alleviates acid suppression of T cells via GPCR68 inhibition and PI3K/AKT/mTOR signal activation, while promoting ferroptosis through the upregulation of Duox1/ROS and suppresseion of NRF2/SLC7A11/GPX4 axis. Therapeutically, BOLT synergizes with anti-CTLA4 blockade to overcome immunotherapy suppression and markedly enhances tumor immunity. These findings establish GPCR68 as a critical pH-sensing regulator of T-cell function and a therapeutic target for pH-based immunomodulation, and propose BOLT as a translational strategy for "alkaline intervention therapy" to potentiate immunotherapy.