1105 HER3 inhibition sensitizes metastatic colorectal and pancreatic cancer to immunotherapy
Year: 2026
Type: conference-abstract
Abstract: Background 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. We subsequently found that this HER3-mediated signaling promotes metabolic reprogramming and lactate production in CRC/PC cells. Since lactate impairs T cell function, this study investigates whether inhibiting the HER3 pathway can enhance immunotherapy efficacy in mCRC/mPC, especially in MSS tumors.Methods Metabolic changes in CRC/PC cells and tumors were first determined by LC-MS and ELISA for key metabolites. Phosphorylation activation of HER3 and downstream metabolic enzymes were evaluated by Western blotting and IHC staining using murine/patient tumor tissues. Syngeneic orthotopic CRC/PC liver metastasis models were established by hepatic injection of murine MSI or MSS cells, with T cell infiltration and function assessed by IHC and flow cytometry. Therapeutic efficacy was assessed in these models treated with HER3 inhibition ( HER3 KO or 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-inhibited tumors showed decreased lactate, which reduced CD8+ T cell exhaustion, as determined by decreased TOX expression, and increased CD8+ T cell cytotoxicity, as determined by increased Granzyme B levels (figure 1). In vitro co-culture assays confirmed that HER3 inhibition enhanced CD8 + T cell cytotoxicity against both CRC/PC cells. Most importantly, the combination of sapitinib with anti-PD-1 achieved ~40% (2/5 mice) tumor-free survival up to 140 days in mCRC, and the combination of HER3 KO and anti-PD-1 led to 100% complete response and tumor-free survival up to 180 days in mPC (5/5 mice), which is markedly superior to monotherapies (figure 2).Conclusions We identify a novel HER3-PFK2-lactate metabolic axis that promotes immunosuppression in CRC/PC liver metastases. Targeting this pathway sensitizes mCRC/mPC to checkpoint blockade, offering a promising strategy to extend immunotherapy benefits beyond the limited patient population currently responsive to ICIs.Acknowledgements We thank Dr. David Wald and Dr. Rebecca Obeng for their expertise in cancer immunology and flow cytometry support. We also thank Dr. Obeng’s lab for technical assistance with flow cytometry experiments.Abstract 1105 Figure 1HER3 inhibition remodels CD8+ T cell differentiation and function in mPCAbstract 1105 Figure 2HER3 inhibition sensitizes mCRC/mPC to immunotherapy
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225168332