Spatial mapping of metabolic drivers of T cell exhaustion in metastatic melanoma

Metastatic melanoma represents a deadly disease with a 10-year survival rate of less than 10%. Immunotherapy is the standard of care for metastatic melanoma, but its success is limited as many patients fail to respond or present different sensitivities between primary tumors and metastasis. This suggests that there may be metastasis-specific mechanisms that locally inhibit CD8+ T cells, leading to exhaustion and loss of anti-cancer function. One of these mechanisms is metabolism. Therefore, this project aims to examine how the metabolic environment of melanoma metastases locally impacts T cell exhaustion. Our initial findings confirm that specific metabolic rewiring occurs under nutrient conditions resembling lung metastasis and that metabolic reprogramming can reverse T cell exhaustion. However, CD8+ T cells’ metabolic demands rely on the distinct inter- and intra-tumor metabolic environments. For this reason, we will utilize imaging spatial metabolomics to profile the metabolic vulnerabilities of exhausted CD8+ T cells in relation to defined metastatic sub-niches. Next, we will enhance CD8+ T cell metabolic fitness, followed by validating the findings in mouse models. Our final goal is to develop strategies for reversing T cell exhaustion and improving the efficacy of immunotherapy for treating metastatic cancer.

Report 2025

Report – Spatial mapping of metabolic drivers of T cell exhaustion in metastatic melanoma

Metastatic melanoma is a highly aggressive cancer often resistant to immunotherapy, leaving patients with few effective treatment options. Identifying combinatorial strategies to enhance current therapies is therefore critical. Our lab has shown that the metabolicenvironment of distant metastases can locally influence CD8+ T cell function and therapy response, highlighting metabolism as a key regulator of immune activity in cancer. However, these insights have largely come from in vitro models, where interactions between cancer and immune cells can be studied in isolation. While valuable, these systems lack the complexity of the in vivo tumor microenvironment. So far, metabolic profiling of entire tumor tissues has not allowed us to resolve localized cell–cell interactions. To move forward, we need spatially resolved metabolic approaches that can reveal how the metastatic niche shapes T cell function and contributes to therapy resistance in vivo . Thanks to the support of the Beug Foundation, we have uncovered a link between metabolic heterogeneity in melanoma-derived lung and liver metastases and distinct patterns of CD8+ T cell infiltration and functionality. These findings suggest that specific metabolic cues within metastatic niches may shape immune responses and contribute to therapy resistance. We are now validating the top candidate metabolites and investigating their mechanistic roles in modulating T cell behavior, with the goal of identifying new targets to overcome resistance and improve immunotherapy outcomes. Importantly, this award has also allowed our lab to generate preliminary data to secure follow up funding.

ilaria.elia@kuleuven.be

www.gbiomed.kuleuven.be