ABSTRACT Melanoma progression is sustained by profound metabolic rewiring and immune suppression within the tumor microenvironment, where adipocyte‐derived lipid droplets (LDs) serve as key metabolic regulators. Here, we exploit this intrinsic biology by engineering resveratrol‐loaded LDs (RSV‐LDs) as natural, lipophilic nanocarriers to drive intracellular delivery and immunometabolic reprogramming. To achieve precise and localized administration, RSV‐LDs were integrated into soluble microneedles, enabling efficient transdermal delivery while minimizing systemic exposure. This strategy markedly increased the M1/M2 macrophage ratio and promoted robust CD8 + T‐cell infiltration, reshaping the immunosuppressive tumor niche. To further potentiate the activity of these infiltrating CD8 + T‐cells, we incorporated ROS‐responsive anti‐PD1 nanoparticles (aPD1‐NPs) via a thioketal linker, enabling tumor‐specific antibody release within the oxidative tumor milieu. Notably, transcriptomic and single‐cell analyses revealed coordinated activation of innate immune and metabolic pathways following treatment, with TLR7/8‐expressing monocytes emerging as a central communication hub among T, NK, and B cell populations. Together, these findings demonstrate that the microneedle‐based RSV‐LD/aPD1 platform induces localized metabolic and immune reprogramming, reshaping the tumor microenvironment to enhance antitumor immunity.
Mahdinloo et al. (Fri,) studied this question.