Dietary restriction remodels the melanoma immune microenvironment and enhances immunotherapy response with spatial association of SELE+ HEVs and NKT-like cells

Dietary restriction (DR) can influence cancer progression by remodeling the tumor microenvironment (TME), but its immunomodulatory effects and underlying mechanisms in melanoma remain incompletely understood. This study aimed to characterize DR-associated transcriptional and cellular changes in melanoma and determine their relevance to prognosis and immunotherapy response. We integrated bulk transcriptomic, single-cell RNA-seq, spatial transcriptomic, and experimental data to establish and validate a transcriptome-derived dietary restriction score (DRS) that quantifies DR-associated transcriptional programs. The association of DRS with clinical outcomes and immunotherapy response was evaluated across multiple cohorts. Mouse melanoma models were used to assess the effects of DR on tumor growth and anti-PD-1 efficacy. Cellular enrichment, functional states, spatial colocalization, and intercellular communication were analyzed to identify DR-responsive cell populations and their potential interactions within the melanoma TME. A high DRS was associated with favorable prognosis and improved response to immunotherapy in human melanoma. In mouse models, DR suppressed melanoma growth through immune-dependent mechanisms and enhanced the therapeutic efficacy of anti-PD-1 treatment. Single-cell and spatial transcriptomic analyses identified cytotoxic natural killer T (NKT)-like cells and SELE⁺ high endothelial venule (HEV) cells as DR-responsive populations enriched in DRS-high tumors. These populations were associated with enhanced anti-tumor immunity and favorable immunotherapy outcomes. Spatial analysis further revealed significant colocalization between NKT-like cells and SELE⁺ HEV cells in DRS-high tumors, whereas this pattern was not observed in DRS-low tumors. Cell-cell communication analysis suggested that SELE⁺ HEV cells may promote NKT-like cell recruitment and activation through ICAM1-ITGAL/ITGB2 signaling. These findings identify a DR-associated immunovascular axis involving SELE⁺ HEV cells and cytotoxic NKT-like cells that may enhance lymphocyte recruitment, activation, and responsiveness to immune checkpoint blockade. The DRS provides a transcriptomic framework for characterizing DR-associated TME remodeling and supports further investigation of dietary restriction as a potential adjunctive strategy for melanoma immunotherapy.