Investigating BCAA oxidation and signaling in macrophages to drive anti-tumor immunity in PDAC

The treatment of pancreatic ductal adenocarcinoma (PDAC) remains a significant challenge, with a 5-year survival rate of just 13%. Resistance to therapies is largely attributed to the immuno-suppressive tumor microenvironment (TME), which is characterized by a fibrotic stroma and high infiltration of immuno- suppressive cells, including tumor-associated macrophages (TAMs), that hinder effector T cell responses. Shifting the immuno-suppressive TAM phenotype toward an immune-activated state presents a promising therapeutic strategy. Previous studies, including our own, suggest that TAM phenotypes are shaped by metabolic pathways. Notably, the metabolism of branched-chain amino acids (BCAAs) has gained attention, as elevated BCAA levels have been associated with more than a twofold increased risk of developing PDAC. While prior research has focused on BCAA metabolism in tumor cells, particularly through the study of BCAA metabolism-related kinases and enzymes, the role of BCAA metabolism in TAMs and its impact on TAM phenotype and anti-tumor immunity remains unexplored. Consequently, it remains unknown whether, and how, this pathway could be therapeutically targeted. Our findings indicated that immuno-suppressive TAMs exhibit reduced BCAA oxidation and reduced incorporation of 13C-labeled BCAAs into the TCA cycle. Increasing BCAA oxidation in TAMs (via BCKDK deletion) enhanced their immuno-stimulatory phenotype, activated CD8+ T cells, and reduced PDAC growth. Conversely, BCAA supplementation induced an immuno- suppressive TAM phenotype and activated the protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway, a key arm of the unfolded protein response. PERK deletion in TAMs reversed this effect, promoting immune activation. Pharmacologically targeting BCAA metabolism—either by increasing BCAA oxidation or inhibiting PERK signaling—enhanced anti-tumor immunity and reduced PDAC growth. Lastly, in patients with solid tumors, high BCAA oxidation and low PERK signaling correlated with better responses to anti-PD1 therapy. We propose that reduced BCAA oxidation and increased BCAA signaling in TAMs drive immuno- suppression in PDAC. Aim 1 will investigate the mechanisms by which BCAA oxidation and BCAA signaling in TAMs differentially influence immune responses in PDAC, focusing on TAM-specific (i) BCAA oxidation via the TCA cycle and OXPHOS, and (ii) BCAA signaling via the PERK pathway. Aim 2 will test whether pharmacologically targeting BCAA metabolism improves chemo-immunotherapy responses in aggressive PDAC mouse models and patient-derived organoids. Successful completion of these objectives will elucidate how TAM-specific BCAA oxidation and BCAA signaling influence immuno-suppressive TAM phenotype. In the long term, this work could lead to novel therapies targeting TAM-specific metabolism for PDAC treatment. Project Number: 1R01CA293027-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Rahul Shinde | Institution: WISTAR INSTITUTE, PHILADELPHIA, PA | Award Amount: $780,764 | Activity Code: R01 | Study Section: Basic Cancer Immunobiology Study Section[BCIB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11298543