Senescence-to-Pyroptosis Nanotuners: Navigating Tumor Inflammatory Microenvironment for Enhanced Immunotherapy

Abstract

Modulating cancer-related chronic inflammation (CCI) is essential to reverse the immunosuppressive tumor microenvironment (TME) for improved therapeutic outcomes. However, the complexity and dynamism of inflammatory processes within the TME pose formidable challenges. Here, we identify senescent tumor cells as a novel "nest"-like target and design a tailored nanotuner that transforms these cells from adversaries to allies in TME remodeling. Specifically, this nanotuner targets metabolic abnormalities and initiates cascading artificial reactions via chemiluminescence resonance energy transfer mechanisms, which trigger self-initiated and self-sustaining photodynamic processes for boosted ¹O₂, converting cellular senescence into pyroptosis. Such conversion fosters multifaceted immune activation, including blocking CCI networks, downregulating PD-L1, and enhancing dendritic cell maturation and T-cell recruitment in tumors. Assessments in two tumor models further demonstrate its durable antitumor effects against primary and distant solid tumors when combined with a PD-1 blockade. This work provides a paradigm shift for novel insights into tumor development and immunoregulatory tactics.