Overcoming cancer immunotherapy barriers via nanomaterial-mediated pyroptosis

Abstract

While cancer immunotherapy has achieved groundbreaking clinical success, its efficacy is frequently compromised by insufficient T-cell activation, the immunosuppressive tumor microenvironment (TME), and off-target toxicity. Pyroptosis, a highly immunogenic form of programmed cell death characterized by gasdermin-mediated pore formation, massive cytokine release (e.g., IL-1β and IL-18), and robust dendritic cell activation, offers a compelling strategy to overcome these limitations. This review critically examines how nanotechnology-enabled pyroptosis induction can potentiate immunotherapy by (1) classifying pyroptosis-inducing nanomaterials into five combinatorial therapeutic platforms – immune checkpoint inhibitors, vaccine adjuvants, oncolytic virus-coupled systems, innate immune sensitizers, and multi-modal hybrids; (2) elucidating their mechanisms in reshaping the TME via pyroptosis-induced immunogenicity and bystander immune cell activation; and (3) highlighting unresolved challenges, including tumor-intrinsic pyroptosis resistance, nanoparticle biodistribution barriers, and cytokine storm risks. By integrating fundamental insights with translational perspectives, this work provides a strategic framework for developing pyroptosis-nanotechnology synergies to achieve precision immune modulation.