Unleashing IFN signal transduction to prime HNSCC immunogenicity

Head and Neck Squamous Cell Carcinoma (HNSCC) is a deadly malignancy with few effective treatment options for patients with advanced disease. While immunotherapy with anti-PD-1 and CTLA-4 have been highly effective in cancers such as melanoma and NSCLC, responses in HNSCC remain low despite a similar tumor mutational burden and features of an inflamed tumor microenvironment. Thus, additional strategies to enhance immune- mediated control of HNSCC are urgently needed. PTPN2 is a phosphatase that inhibits JAK-STAT signaling in tumor cells and immune cells. We previously identified PTPN2 inhibition (PTPN2i) as a therapeutic approach that renders tumor cells highly sensitive to interferon. We recently described the development of the first small molecule inhibitor of PTPN2 and described its efficacy and mechanism of action as an immunotherapy in tumor models. In preliminary studies, we discovered that inhibition of PTPN2 in HNSCC cells treated with IFNg dramatically increases the expression of STING and that combination treatment of tumor cells with PTPN2i and STING agonist led to synergistic activation of type I IFN responses and cell death. Further, our preliminary data suggests that PTPN2i and STING agonism could also synergistically activate NK cell anti-tumor immunity and rescue T cells from STING agonist toxicity. These observations form the foundation of our proposal to study the combination efficacy of these therapies in preclinical models and patient tumor explants. Specifically, we propose to: 1) investigate the mechanism of PTPN2-mediated elevation of STING levels in tumor cells and how the signaling pathways engaged by each of the therapies synergistically activates IFN responses and cell death; 2) determine the preclinical safety and efficacy of this combination therapy across a range of HNSCC mouse models and patient tumor explants, while using deep profiling of the tumor microenvironment to understand how combining these agents impacts the TME; and 3) investigate the hypothesis that the combination of STING agonists and PTPN2i will synergistically enhance the infiltration, effector function, and survival of NK cells and T cells. These studies will not only advance our understanding of this novel therapeutic combination, but will provide new insights into how the modulation of innate immune signaling pathways in cancer can be leveraged to engage cellular innate and adaptive immunity. Project Number: 1R01CA312510-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Robert Manguso (+1 co-PI) | Institution: BROAD INSTITUTE, INC., CAMBRIDGE, MA | Award Amount: $742,382 | Activity Code: R01 | Study Section: Therapeutic Immune Regulation Study Section[TIR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11347426