Targeting myeloid-derived suppressor cells (MDSCs) to restore antitumor immunity in non-small cell lung cancer (NSCLC) via SRC family kinase Inhibition with NXP900

Background: Despite therapeutic advances, non-small cell lung cancer (NSCLC) demonstrates poor survival outcomes, with global 5-year rates of only ~ 16 - 19%. The tumor microenvironment (TME) critically influences NSCLC prognosis and treatment response through immune contexture (cell type, density, and spatial location). Elevated CD4⁺ and CD8⁺ T-cell tumor infiltration correlates with improved survival. Contrastingly, increased myeloid-derived suppressor cells (MDSCs) promote immune evasion, angiogenesis, and metastasis. NXP900 (eCF506) is a highly potent and selective SRC family kinase (SFK) inhibitor (IC 50 of 0.47 nM against YES1) that locks SFKs in their inactive “closed” conformation (type 1.5), inhibiting both enzymatic and scaffolding activities of SFKs. Cancer models exhibiting hippo pathway modulators such as FAT1 or NF2 mutation or loss are associated with increased sensitivity to NXP900 in vitro and tumor growth inhibition and regression in vivo . Given MDSC dependence on SFKs and YAP/TAZ signaling required for immunosuppressive function, we hypothesized that NXP900 may suppress MDSCs, thereby reversing immune suppression, and enhance antitumor immunity in NSCLC. Methods: Tumor and immune cell morphology were analyzed in 162 chemotherapy-naïve, early-stage NSCLC adenocarcinomas. Multiplex immunofluorescence (mIF) was performed on a subcohort (n=60) using lymphocyte (CD4, CD8 and CD20) and MDSC panels (CD11b, CD14 and CD15), with population and spatial analysis performed using HALO ® software. Induced MDSCs (iMDSCs) were validated in vitro via flow cytometry and RT-PCR, treated with NXP900 for 48 hours, and immunostained for YAP1, YES1, phalloidin, and Hoechst and analyzed. Viability was assessed using Presto Blue assay. Results: Immune high NSCLC patients showed longer overall survival compared with immune low patients (HR = 1.763; 95% CI, 1.098-2.830; *p = 0.03). Elevated MDSC populations negatively correlated with survival (HR, 0.5456; 95% CI, 0.2355-1.265; * p = 0.04) and exhibited contact-dependent suppression of effector T cells. NXP900 treatment depleted iMDSCs, reduced YAP1 phosphorylation and nuclear localization in a dose-dependent manner, and demonstrated pro-immune effects consistent with inhibition of hippo pathway modulation. Conclusions: These findings identify MDSCs as a key immunosuppressive driver of prognostic significance in NSCLC. NXP900 currently in a Phase 1b study (NCT05873686) including in NSCLC patients with YES1 and FAT1 genomic alterations, effectively suppresses MDSC viability and YAP1 signaling in vitro, supporting its potential as a novel therapy in NSCLC.