Growth hormone receptor antagonism improves tumoral chemo-immunotherapy response in a mouse model of lung cancer

Despite the clinical success of immune checkpoint inhibitors (ICIs), most patients with non–small cell lung cancer (NSCLC) fail to achieve durable responses due to intrinsic and acquired resistance. Growth hormone (GH) receptor (GHR) signaling has been implicated in tumor progression and therapy resistance, but its role in shaping anti-tumor immunity and chemo-immunotherapy response in NSCLC is unknown. To address this, syngeneic murine lung tumors were established in wild-type (WT) and GH antagonist transgenic (GHA) mice and treated with cisplatin, anti–PD-1 antibody, or their combination. Additionally, tumor growth was monitored longitudinally, while systemic and intratumoral insulin-like growth factor-1 (IGF-1) levels were quantified by ELISA. Tumor tissues were further analyzed by western blotting to assess immune checkpoint molecules, chemokine signaling components, and mediators of therapeutic resistance, and fibrotic remodeling was quantified using a hydroxyproline assay. High tumoral GHR expression was positively correlated with transcriptional signatures of therapy resistance, including ABC transporters, EMT markers, and ECM remodeling factors, and inversely associated with immune activation pathways. However, GHR antagonism in combination with cisplatin and anti–PD-1 therapy significantly suppressed tumor growth and enhanced therapeutic efficacy. Importantly, the combination of GHR blockade selectively increased PD-L1, PD-L2, and PD-1 expression, enhanced CXCL10–CXCR3 signaling, and downregulated the mediators of tumoral drug resistance and stromal remodeling. Therefore, we present the first indications that GHR signaling promotes immune suppression, therapy resistance, and fibrotic remodeling in NSCLC and support pharmacologic GHR antagonism as a novel strategy to sensitize tumors to chemo-immunotherapy.