48 Metabolic Control of Tumor Immunity Through Lipid Remodeling in FH-Deficient Renal Cancer

Background Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is an aggressive metabolic subtype of kidney cancer characterized by fumarate accumulation and profound rewiring of mitochondrial metabolism. While FH loss is known to promote reductive carboxylation and lipid synthesis, how these metabolic changes influence tumor immunity remains unclear. Methods To investigate the relationship between lipid metabolism and immune signaling in FH-deficient RCC, we performed lipidomic profiling of FH-deficient patient tumors and normal kidney tissue, spatial transcriptomic analyses of patient samples, and functional studies using FH-deficient patient-derived and murine tumor models. ACL inhibition was used to evaluate the role of lipid metabolic state in ferroptotic sensitivity and innate immune signaling. Results FH-deficient tumors demonstrated enrichment of polyunsaturated fatty acid (PUFA)-containing phospholipids, consistent with mitochondrial and redox stress. Spatial analyses of patient tumors revealed that cGAS-STING-associated signaling is activated in FH patient tumors despite variable immune infiltration, suggesting coexistence of immune activation and suppression within the tumor microenvironment. Given the role of ATP citrate lyase (ACL) in regulating lipid synthesis and PUFA accumulation, we examined whether ACL activity modulates these immune states. In FH-deficient patient-derived cell lines, ACL inhibition increased ferroptotic vulnerability and induced mitochondrial DNA release into the cytosol, while restoration of FH reduced this sensitivity. Similar FH-dependent responses to ACL inhibition were observed in murine tumor models. To further study immune-metabolic interactions in vivo, we established syngeneic organoid-derived FH-deficient RCC models that retain proximal tubular identity. Conclusions Our findings support a model in which FH loss drives PUFA-enriched lipid remodeling that may shape the tumor immune state through ferroptotic stress and cGAS-STING-associated signaling. These studies identify ACL as a potential metabolic regulator linking lipid metabolism to anti-tumor immunity in FH-deficient RCC and establish new immune-competent models for mechanistic investigation. DOD CDMRP Funding yes