Advancing tumor immunotherapy through rationally engineered inorganic nanomaterials

Although tumor immunotherapy has demonstrated significant clinical efficacy, its therapeutic outcomes are still limited by factors such as immune escape mechanisms, immune tolerance, weak immunogenicity, and patient-specific differences. In recent years, inorganic nanomaterials have emerged as a multifunctional and promising tool to sensitize tumor immunotherapy, which orchestrates immunotherapeutic agent for amplified tumor therapeutic outcome. Beyond serving as drug carriers, inorganic nanomaterials possess numerous advantageous properties such as stimuli-responsive biodegradation, tunable physiochemical properties, intrinsic catalytic, optical, magnetic or ultrasonic characteristics, which enables their intrinsic immunostimulatory properties through directly activating immune cells, augmenting the sensitiveness of immune cells to stimuli, upregulating immune checkpoint expression, or inducing immunogenic cell death (ICD), creating natural synergies with existing immunotherapy paradigms. This review systematically examines the interplay between physicochemical properties of inorganic nanomaterials and their immunomodulatory functions in tumor immunotherapy, elucidating the underlying molecular mechanisms that govern their immune-enhancing effect. We also highlight the emerging strategies that engineer inorganic nanomaterials for optimized efficacy in tumor immunotherapy. Furthermore, the combinatorial strategies and perspectives on the challenges facing clinical adaptation of inorganic nanomaterials-based tumor immunotherapeutics are discussed. This work provides fundamental insights to guide the rational design of next-generation immunotherapy platforms based on inorganic nanomaterials. STATEMENT OF SIGNIFICANCE: The therapeutic outcomes of tumor immunotherapy are limited by insufficient immune activation. Inorganic nanomaterials themselves may have low immunogenicity, but they have emerged as a powerful tool to potentiate tumor immunotherapy through multiple mechanisms. In this study, we summarize the underlying molecular mechanisms and the emerging advanced strategies that engineer inorganic nanomaterials for optimized efficacy in tumor immunotherapy. The combinatorial strategies and perspectives on the challenges facing clinical adaptation of inorganic nanomaterials-based tumor immunotherapeutics are also discussed. This work provides insights for the rational design of inorganic nanomaterials for enhanced tumor immunotherapy.