Restoring antitumor immunity by reprogramming abnormal lipid metabolism in the tumor microenvironment using irisin-manganese co-loaded nanoparticles

Targeting dysregulated lipid metabolism within the tumor microenvironment (TME) has emerged as a promising strategy for restoring anti-tumor immunity and reversing immune suppression to improve therapeutic efficiency. This study reports a nanomaterial platform for co-delivery of irisin and manganese ions (Mn²⁺) to exert cumulative effects of modulating lipid metabolism dysregulation and ameliorating the immunosuppressive TME in triple-negative breast cancer (TNBC). Irisin stimulates lipolysis and inhibits lipogenesis, whereas Mn²⁺ strengthen irisin binding to integrin αVβ5 over-expressed in various cancers. Developed manganese-containing mesoporous organosilica nanoparticles (MMONs) loaded with irisin (MMONs-irisin) were stable in physiological conditions but enabled pH responsive release of irisin and glutathione (GSH) responsive release of Mn²⁺ within the TME in a murine model of TNBC. Together, irisin and Mn²⁺ effectively reduced intracellular lipid droplets (LDs) across different cell types in vitro as well as intratumoral LDs in TME, thereby reprogramming dysregulated lipid metabolism and subsequently enhancing the antigen presentation in dendritic cells (DCs) and antigen-specific cytotoxicity of CD8⁺ T cells. Concomitantly, MMONs-irisin significantly increased immunogenicity of TNBC, involving activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway following depletion of LDs. Together, MMONs-irisin effectively delivers a coordinated cascade of immune-potentiating effects to disrupt immunosuppressive TME and restore anti-tumoral immunity, significantly improving the treatment responses of anti-programmed cell death protein 1 (aPD-1). STATEMENT OF SIGNIFICANCE: Dysregulated lipid metabolism in the tumor microenvironment suppresses antitumor immunity. However, existing lipid-targeting strategies remain confined to specific cell types and are limited by systemic toxicity. To address this challenge, we developed irisin-manganese co-loaded nanoparticles that reprogram abnormal lipid metabolism in triple-negative breast cancer. This intervention restores tumor cell immunogenicity, dendritic cell antigen presentation, and CD8⁺ T cell cytotoxicity, thereby augmenting antitumor immune responses and potentiating the efficacy of anti-PD-1 therapy. These findings underscore a biomaterial-based strategy to overcome metabolic immune suppression and enhance cancer immunotherapy.