RORγt Inhibition Reduces Pro-Tumor Inflammation and Decreases Tumor Growth in Experimental Models of Lung Cancer Available to Purchase

The retinoic acid receptor-related orphan receptor C (RORC) gene encodes two isoforms, RORγ and RORγt, which function as transcription factors in different cell types. RORγt is expressed in specific immune cells involved in inflammatory responses, while RORγ is found in parenchymal cells, where it participates in metabolism and circadian rhythm regulation. Although the roles of RORγt in CD4+ T-helper 17 (Th17) lymphocytes and RORγ in certain cancer cell types are increasingly recognized, their relative contributions to lung cancer (LC) development remain unclear. In this study, we investigated the roles of RORC, RORγ, and RORγt in LC using mouse models and human data from The Cancer Genome Atlas (TCGA). We evaluated the effects of Rorc gene deletion and RORγ/γt pharmacological inhibition in cancer and immune cells in vitro and in vivo. Pharmacological blockade of RORγ/γt with digoxin significantly reduced LC development in two mouse models: a KrasG12D-driven genetic model and a urethane-induced chemical model. Mechanistically, this effect was mediated by inhibition of RORγt in specific immune cells, such as type 3 innate lymphoid cells (ILC3s) and Th17 cells, rather than by inhibiting RORγ in tumor cells. This reduced the production of pro-inflammatory cytokines, including interleukin-17A (IL-17A), IL-17F, and IL-22, and decreased tumor cell proliferation. Additionally, TCGA analysis revealed that elevated RORC expression is associated with an altered tumor microenvironment (TME) and poorer prognosis in patients with lung adenocarcinoma (LUAD). These findings highlight the therapeutic potential of targeting RORγt to reduce pro-tumor inflammation and propose a strategy for LC treatment.