A Ca-Mg Synergistic Agonist for Trade-off CD8 T Cell Immunomodulation to Enhance Solid Tumor Immunotherapy
Abstract
Adjuvants have traditionally been developed to activate antigen-presenting cells and thereby initiate adaptive immunity. Emerging evidence, however, indicates that adjuvants can also directly regulate T lymphocyte function. Here, we report a calcium-magnesium nano-aluminum adjuvant (CMA) that functions as a self-braking CD8+ T cell agonist. By integrating complementary immunoregulatory activities of Ca2+ and Mg2+ within nano-aluminum platform, CMA dynamically modulates CD8+ T cell activation and exhaustion to enhance the effector function. Following efficient cellular internalization, CMA enhances CD8+ T cell activity under both physiological and lactic acid (LA)-rich conditions that mimic the tumor microenvironment. Mechanistically, CMA promotes oxidative phosphorylation and activates NFAT2 signaling to increase production of effector molecules, including interferon-γ and granzyme B. Concurrently, CMA suppresses AKT phosphorylation, preserves proteostasis, and attenuates the expression of exhaustion-associated inhibitory receptors. As a result, ex vivo CMA pretreatment endows CD8+ T cells with sustained functionality and resistance to LA-mediated immunosuppression, leading to improved antitumor efficacy following adoptive cell transfer. In parallel, local administration of CMA directly activates tumor-resident CD8+ T cells and suppresses tumor growth. Combining adoptive transfer of CMA-primed CD8+ T cells with peritumoral CMA administration produces superior therapeutic efficacy against solid tumors. Collectively, this work establishes a biomaterial-based strategy for direct CD8+ T cell regulation and highlights nano-engineered adjuvants as a versatile platform for enhancing cancer immunotherapy through dynamic control of T cell activation and exhaustion.
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