Stimulator of Interferon Genes Pathway Activation through the Controlled Release of STINGel Mediates Analgesia and Anti-Cancer Effects in Oral Squamous Cell Carcinoma
Minh Phuong Dong,
Neeraja Dharmaraj,
Estela Kaminagakura,
Jianfei Xue,
David G. Leach,
Jeffrey D. Hartgerink,
Michael Zhang,
Hana-Joy Hanks,
Yi Ye,
Bradley E. Aouizerat,
Kyle Vining,
Carissa M. Thomas,
Sinisa Dovat,
Simon Young,
Chi T. Viet
Affiliations
Minh Phuong Dong
Department of Oral and Maxillofacial Surgery, School of Dentistry, Loma Linda University, Loma Linda, CA 92350, USA
Neeraja Dharmaraj
Katz Department of Oral Maxillofacial Surgery, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
Estela Kaminagakura
Department of Biosciences and Oral Diagnosis, Institute of Science and Technology, São Paulo State University (Unesp), São Paulo 12245-00, Brazil
Jianfei Xue
Katz Department of Oral Maxillofacial Surgery, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
David G. Leach
Department of Chemistry, Rice University, Houston, TX 77005, USA
Jeffrey D. Hartgerink
Department of Chemistry, Rice University, Houston, TX 77005, USA
Michael Zhang
Department of Oral and Maxillofacial Surgery, School of Dentistry, Loma Linda University, Loma Linda, CA 92350, USA
Hana-Joy Hanks
Department of Oral and Maxillofacial Surgery, School of Dentistry, Loma Linda University, Loma Linda, CA 92350, USA
Yi Ye
Translational Research Center, Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, NY 10010, USA
Bradley E. Aouizerat
NYU Pain Research Center, Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA
Kyle Vining
Department of Preventive and Restorative Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Carissa M. Thomas
Department of Otolaryngology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Sinisa Dovat
Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
Simon Young
Katz Department of Oral Maxillofacial Surgery, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
Chi T. Viet
Department of Oral and Maxillofacial Surgery, School of Dentistry, Loma Linda University, Loma Linda, CA 92350, USA
Oral squamous cell carcinoma (OSCC) presents significant treatment challenges due to its poor survival and intense pain at the primary cancer site. Cancer pain is debilitating, contributes to diminished quality of life, and causes opioid tolerance. The stimulator of interferon genes (STING) agonism has been investigated as an anti-cancer strategy. We have developed STINGel, an extended-release formulation that prolongs the availability of STING agonists, which has demonstrated an enhanced anti-tumor effect in OSCC compared to STING agonist injection. This study investigates the impact of intra-tumoral STINGel on OSCC-induced pain using two separate OSCC models and nociceptive behavioral assays. Intra-tumoral STINGel significantly reduced mechanical allodynia in the orofacial cancer model and alleviated thermal and mechanical hyperalgesia in the hind paw model. To determine the cellular signaling cascade contributing to the antinociceptive effect, we performed an in-depth analysis of immune cell populations via single-cell RNA-seq. We demonstrated an increase in M1-like macrophages and N1-like neutrophils after STINGel treatment. The identified regulatory pathways controlled immune response activation, myeloid cell differentiation, and cytoplasmic translation. Functional pathway analysis demonstrated the suppression of translation at neuron synapses and the negative regulation of neuron projection development in M2-like macrophages after STINGel treatment. Importantly, STINGel treatment upregulated TGF-β pathway signaling between various cell populations and peripheral nervous system (PNS) macrophages and enhanced TGF-β signaling within the PNS itself. Overall, this study sheds light on the mechanisms underlying STINGel-mediated antinociception and anti-tumorigenic impact.
