Dietary restriction reshapes melanoma immune landscape and may boost immunotherapy response

Dietary restriction appears to reshape the immune landscape of melanoma tumors in ways that may improve responses to immunotherapy, according to a study published in Genome Medicine. Researchers built a transcriptome-derived dietary restriction score (DRS) that quantifies diet-associated gene programs in tumors, and found that a high DRS was associated with both favorable prognosis and improved response to immunotherapy in human melanoma cohorts.

The study integrated bulk transcriptomic, single-cell RNA-seq, spatial transcriptomic, and experimental data to establish and validate the DRS. To test whether dietary restriction has a causal role rather than a mere association, the team turned to mouse melanoma models. In these models, dietary restriction suppressed melanoma growth through immune-dependent mechanisms and enhanced the therapeutic efficacy of anti-PD-1 treatment, an immune checkpoint blockade therapy.

Single-cell and spatial transcriptomic analyses identified two cell populations that were enriched in tumors with high DRS: cytotoxic natural killer T (NKT)-like cells and SELE-positive high endothelial venule (HEV) cells. Both DR-responsive populations were associated with enhanced anti-tumor immunity and favorable immunotherapy outcomes.

A key finding came from spatial analysis. In tumors with high DRS, NKT-like cells and SELE-positive HEV cells showed significant colocalization, meaning the two populations were physically close to one another within the tumor microenvironment. This spatial pattern was not observed in tumors with low DRS, suggesting that the proximity of these immune and vascular compartments is a distinctive feature of the diet-associated tumor state.

Cell-cell communication analysis suggested a possible mechanism behind this spatial relationship: SELE-positive HEV cells may promote the recruitment and activation of NKT-like cells through ICAM1-ITGAL/ITGB2 signaling.

The authors conclude that these findings identify a DR-associated immunovascular axis involving SELE-positive HEV cells and cytotoxic NKT-like cells that may enhance lymphocyte recruitment, activation, and responsiveness to immune checkpoint blockade. The DRS itself offers a transcriptomic framework for characterizing dietary restriction-associated remodeling of the tumor microenvironment, and the researchers position it as a tool to support further investigation of dietary restriction as a potential adjunctive strategy for melanoma immunotherapy.

The study, published on 23 October 2026 as an open-access research article in Genome Medicine, was led by Qian Liu, Jia Guo and Lin Zhu as co-first authors, with Guanxiong Zhang among the authors. The team notes that the immunomodulatory effects and underlying mechanisms of dietary restriction in melanoma were previously incompletely understood, and that their work was designed to characterize DR-associated transcriptional and cellular changes and determine their relevance to prognosis and immunotherapy response.

Because the human findings are based on associations between a transcriptomic score and clinical outcomes across multiple cohorts, while the causal evidence comes from mouse models, the results support further investigation rather than immediate clinical application. The researchers emphasize that the DRS provides a framework for characterizing DR-associated tumor microenvironment remodeling and that dietary restriction remains a potential adjunctive strategy to be tested in the context of melanoma immunotherapy.

Subject of Research: Dietary restriction-associated remodeling of the melanoma tumor immune microenvironment and its association with immunotherapy response

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

Article References: Liu, Q., Guo, J., Zhu, L., Chen, J., He, Z., Chen, X., Liu, H., Xu, L., & Zhang, G. (2026). Dietary restriction remodels the melanoma immune microenvironment and enhances immunotherapy response with spatial association of SELE+ HEVs and NKT-like cells. Genome Medicine. https://doi.org/10.1186/s13073-026-01808-6

Image Credits: AI Generated

DOI: 10.1186/s13073-026-01808-6

Keywords: dietary restriction, melanoma, tumor microenvironment, immunotherapy, anti-PD-1, NKT-like cells, high endothelial venules, SELE, spatial transcriptomics, immune checkpoint blockade, single-cell RNA-seq, Genome Medicine