OBJECTIVE: Regulatory Factor X (RFX) transcription factors have been implicated in different cancers. Ras association domain family (RASSF) has been shown clinical significance in lung cancer. This paper was to investigate the interaction of RFX2 and RASSF1 in lung adenocarcinoma (LUAD). METHODS: The transcriptome differences of LUAD patients in GSE32863, GSE43458, and GSE21933 datasets were analyzed. A-549 and NCI-H358 cell lines after overexpression of RFX2 were co-cultured with activated CD8 RESULTS: RFX2 was notably downregulated in LUAD. RFX2 overexpression increased infiltrating CD8 CONCLUSION: RFX2 Loss in LUAD downregulates RASSF1 expression and YAP phosphorylation, thereby promoting immune escape through Hippo signaling.