A pH-responsive liposomal nanoplatform for reprogramming lactate metabolism and immunogenic activation in pancreatic cancer.

Abstract

Pancreatic cancer is characterized by excessive lactate accumulation, which establishes a profoundly immunosuppressive tumor microenvironment (TME) and limits the efficacy of immunotherapy. Here, we identify lactate-driven immune suppression as a central barrier to antitumor immunity, which is difficult to effectively modulate in vivo due to poor intratumoral drug delivery, and develop a pH-responsive liposomal nanoplatform (S&P@RL) to simultaneously enhance tumor immunogenicity and relieve metabolic immune suppression. S&P@RL co-delivers Polyphyllin VI (PPVI), which induces pyroptosis, immunogenic cell death (ICD), and STING activation, and Syrosingopine (Syro), an MCT4 inhibitor that blocks lactate efflux. RGD-mediated targeting and acid-labile hydrazone cleavage enable enhanced intratumoral distribution and microenvironment-triggered drug release. In pancreatic cancer models, S&P@RL markedly reduced intratumoral lactate levels, promoted the maturation of dendritic cells (DCs), enhanced CD8⁺ T-cell and natural killer (NK) cell infiltration, and reprogrammed macrophages toward an M1 phenotype while suppressing regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs). Consequently, tumor growth and lung metastasis were significantly inhibited. Notably, S&P@RL sensitized pancreatic cancer to PD-1 blockade, effectively converting immunologically "cold" tumors into "hot" tumors without systemic toxicity. This study establishes a biomaterial-enabled strategy that integrates metabolic reprogramming and immune activation to overcome immune resistance in pancreatic cancer.