Inhibiting Lactylation‐Mediated Metabolic‐Epigenetic Reprogramming to Potentiate Tumor Photo‐Immunotherapy

Cancer immunotherapies face limitations in treating "cold" tumors due to immune suppression driven by metabolic dysregulation within the tumor microenvironment. Research has revealed that tumor cells produce excess lactate via hypoxia-induced glycolysis, promoting histone lactylation and establishing immunosuppression-associated metabolic-epigenetic reprogramming. Here, a near-infrared (NIR)-triggered nanoplatform (RgA-L-I/P/R) has been developed to fundamentally dismantle the immunosuppression via the metabolic-epigenetic axis. Upon NIR excitation, the platform released oxygen from perfluoropentane (PFP) ("oxygen unlocking chamber") in the tumor through dual targeting of AS1411 and Rg3 ("nano-warhead"), liberating the IR-1048 and the CRISPR/Cas9 ribonucleoprotein (RNP) ("NIR immune trigger" and "metabolic nanolock"). IR-1048 induced immunogenic cell death (ICD) to trigger dendritic cell maturation and cytotoxic T lymphocyte infiltration, while CRISPR/Cas9 RNP induced LDHA (lactate dehydrogenase A) gene knockdown that locked the lactate supply and reprogrammed metabolism and epigenetics. These changes reduced histone lactylation and IL-10 expression, promoting the conversion of tumor-associated macrophages to the M1 type and synergistically downregulating hypoxia-inducible factor-1α (HIF-1α) and programmed death-ligand 1 (PD-L1) expression upon oxygen release. This nanoplatform enables synergistic photothermal immunostimulation with CRISPR-mediated metabolic and epigenetic reprogramming. Rather than merely countering mild downstream immune regulation by ICD, it seeks to fundamentally eliminate the immunosuppression, offering novel therapeutic strategies through the metabolic-epigenetic pathway for poorly immunoresponsive tumors.