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

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/fl CD4 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. • GPCR68 acts as a pH-sensing immune checkpoint of acidosis-driven immune suppression in T cells. • An injectable borate-optimized local tumor therapy (BOLT) strategy is engineered to exert effective anti-tumor response. • BOLT activates T cell immunity by inhibiting GPCR68 and activating PI3K-AKT-mTOR axis. • BOLT induces tumor cell ferroptosis via Duox1-ROS-Nrf2-SLC7A11 pathway. • BOLT reprograms the acidic tumor microenvironment (TME) to improve anti-CTLA-4 immunotherapy response. Significance: The acidic tumor microenvironment (TME) activates the proton-sensing receptor GPCR68, thereby suppressing T-cell activation and effector function. Here, we have engineered BOLT, an injectable borate-optimized local tumor therapy that remodels tumor acidity toward mild extracellular alkalinization, suppresses GPCR68 signaling to restore antitumor T-cell function, and induces tumor cell ferroptosis. These findings establish alkaline intervention therapy as a mechanistically grounded strategy for tumor treatment and for potentiating cancer immunotherapy.