Lung Adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide, and identifying drivers of immunosuppression in KRAS-mutant tumors is a critical priority. Here, we identify Cardiotrophin-like cytokine factor-1 (CLCF1) as a cytokine upregulated in LUAD patients, where it correlates with poor overall survival. While combined inhibition of CLCF1 and PD-1 shows clinical promise, the cellular mechanisms underlying this synergy are not fully defined.

Using a computational pipeline, we mapped a prognostic gene signature derived from TCGA-LUAD data onto a single-cell atlas of human lung cancer, identifying mregDCs (mature dendritic cells enriched in immunoregulatory molecules) as a primary population with maximal signature enrichment. We validated these findings in vivo using the Kras^LSL-G12D/+ ;Trp53^fl/fl  (KP) mouse model and performing high-parameter flow cytometry following anti-CLCF1 treatment. Notably, CLCF1 blockade significantly reduced PD-L1 surface expression and modulated CD80 levels specifically within the mregDC compartment.

In conclusion, this suggests that CLCF1 contributes to the maintenance of an inhibitory tumor microenvironment (TME) by modulating the mregDC-PD-L1 axis. Our results provide a preliminary mechanistic basis for the observed synergy with anti-PD1 therapy, highlighting CLCF1 as a potential target for enhancing immunotherapy efficacy in KRAS-driven lung cancer.