STING-induced cytokine profiles in tumor fragments correlate with recurrence in head and neck cancer patients

Only about 20% of head and neck squamous cell carcinoma (HNSCC) patients respond to immune checkpoint blockade (ICB), underscoring the need for alternative immunotherapeutic strategies and functional assays to assess patient-specific immune function. Activation of the stimulator of interferon genes (STING) pathway has emerged as a promising, tumor-agnostic approach capable of enhancing cytotoxic immune activity and overcoming ICB resistance. Our lab previously developed PolySTING, a polymeric STING agonist whose efficacy is mediated by cDC1-driven myeloid activation. To assess interpatient heterogeneity in STING responsiveness, we established an ex vivo patient-derived tumor fragment (PDTF) platform using resected HNSCC specimens that preserves native tumor architecture and resident immune populations. Cytokine profiling of tumor fragments following PolySTING treatment revealed distinct immune response phenotypes across patients, associated with innate immune signaling, adaptive immune activation, or acute inflammatory states . These immune response phenotypes correlated with the baseline immune composition of each tumor and, notably, with clinical outcomes, particularly post-surgical recurrence in the source patients. Our findings suggest that ex vivo STING perturbation of HNSCC tumor fragments captures clinically relevant immunosuppressive states and provide a functional biomarker to identify patients at risk of post-surgical recurrence. - References: Wang J, Li S, Wang M, et al. STING licensing of type I dendritic cells potentiates antitumor immunity. Science Immunology. 2024;9(92). Voabil P, De Bruijn M, Roelofsen LM, et al. An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer. Nature Medicine. 2021;27(7):1250-1261. Chen S, Pyne JM, Liu Y, et al. Nodal Yield From Neck Dissection Predicts the Anti‐Tumor Immune Response in Head and Neck Cancers. Head & Neck. 2025;47(4):1199-1208.