HER3 inhibition sensitizes metastatic colorectal and pancreatic cancer to immunotherapy

INTRODUCTION: Metastatic colorectal cancer (mCRC) and pancreatic cancer (mPC) demonstrate 5-year survival rates of 14% and 3%, respectively, with over 70% patients developing distant metastases in the liver. Immune checkpoint inhibitors (ICIs) exhibit significant efficacy in some solid tumors and MSI CRC but have limited therapeutic benefit in MSS mCRC/mPC. This project aims to identify potential novel combination strategies to overcome ICIs resistance in mCRC/mPC. We previously discovered that liver endothelial cells activate HER3 signaling in cancer cells through NRG1 and LRG1 ligands, promoting metastatic growth via distinct AKT/RSK pathways. This study investigates whether inhibiting HER3 pathway can enhance immunotherapy efficacy in mCRC/mPC, especially MSS tumors. METHODS: Metabolic changes in CRC/PC cells and tumors were first determined by LC-MS and ELISA for key metabolites, and then further assessed by in vitro assays, including Seahorse FX and TMRE, in the context of HER3 activation and/or inhibition. Phosphorylation activation of HER3 and downstream metabolic enzymes were evaluated by Western blotting and IHC staining using murine/patient tumor tissues. We developed syngeneic, orthotopic CRC/PC liver metastases by hepatic injection of murine CRC and PC cells (MSI or MSS), and assessed T cell infiltration and activation by IHC staining and flow cytometry. More importantly, therapeutic efficacy was assessed by treating these models with HER3 inhibitor sapitinib and/or anti-PD-1 antibodies. RESULTS: LC-MS analysis revealed that mCRC/mPC exhibited significantly elevated glycolytic metabolites compared to primary tumors, with HER3 inhibition reversing this metabolic reprogramming. HER3 activation enhanced phosphofructokinase 2 (PFK2)-S483 phosphorylation and increased lactate secretion in CRC/PC cells. In murine CRC/PC liver metastases, HER3 KO tumors showed decreased lactate, which reduced exhaustion of CD8 + T cells, determined by decreased expression of TOX, and increased cytotoxic CD8 + T cells, determined by increased Granzyme B levels. Most importantly, the combination of HER3 inhibition with anti-PD-1 significantly extended survival in CRC/PC liver metastases (both MSI and MSS), and achieved ~40% complete response rate, which is markedly superior to monotherapies. CONCLUSIONS: We identify a novel HER3-PFK2-lactate metabolic axis that promotes immunosuppression in CRC/PC liver metastases. Targeting this pathway sensitizes CRC/PC liver metastases to checkpoint blockade, offering a promising strategy to extend immunotherapy benefits beyond the limited patient population currently responsive to ICIs.