Ionic immune checkpoint blockade through potassium-scavenging hydrogel to potentiate CD8⁺ T cell-mediated cancer immunotherapy.

Abstract

Immunotherapy efficacy is constrained by immunosuppressive features of the tumor microenvironment (TME) beyond canonical molecular checkpoints, including emerging extracellular ionic regulatory mechanisms that remain poorly characterized. Here, we identify potassium ion (K⁺) as a metabolically coupled ionic immune checkpoint that suppresses CD8⁺ T cell antitumor immunity. Using a murine melanoma model with an elevated-K⁺ microenvironment, we demonstrate that excess extracellular K⁺ profoundly impairs CD8⁺ T cell proliferation, activation, and effector function while promoting functional exhaustion without reducing T cell abundance. Mechanistically, K⁺-mediated immunosuppression is accompanied by restricted glucose uptake, suppressed glycolytic flux, and impaired mitochondrial fitness, establishing metabolic insufficiency as a key basis for ionic checkpoint-driven T cell dysfunction. To therapeutically target this extracellular and non-molecular suppressive mechanism, we develop a localized K⁺-depleting strategy by encapsulating the clinically approved potassium-binding agent sodium zirconium cyclosilicate (ZS-9) within a thermosensitive poly (lactide-co-glycolide)-polyethylene glycol-poly (lactide-co-glycolide) (PLGA-PEG-PLGA) hydrogel, forming a peritumoral K⁺-scavenging depot. This biomaterial platform efficiently remodels the ionic TME, restores CD8⁺ T cell metabolic fitness and effector function, alleviates T cell exhaustion, and significantly enhances the antitumor efficacy of adoptive cell therapy (ACT). Collectively, this work establishes extracellular ionic modulation as a metabolically grounded immune checkpoint mechanism and highlights biomaterials-based ionic remodeling as a translatable strategy to augment cancer immunotherapy.