Simple SummaryPulmonary sarcomatoid carcinoma (PSC) is an aggressive subtype of non-small-cell lung cancer (NSCLC). It does not respond favorably to standard chemotherapy, and the response to PD-1/PD-L1 inhibitors remains modest. The introduction of new therapeutic approaches for this subtype is crucial. Our study demonstrates that PD-L1 expression was significantly higher in the epithelial component than in the sarcomatoid component. Expression of PD-L1 in both components was only seen in 32.1% of patients. However, the majority of PSC patients had at least one immune checkpoint expression in both components. Thus, combination immune checkpoint inhibition based on expression profiles may prove as a personalized and effective treatment strategy. This study also reveals a high rate ofMETexon 14 skipping mutation (METex14) in PSC.METex14 selectively induced PD-L1 expression through MAPK or PI3K/Akt pathways. A combination of targeted therapies with immunotherapy in this population also warrants further investigation as a novel treatment approach.AbstractImmunotherapy has transformed lung cancer management, but PSC remains an aggressive subtype with a poor prognosis. This study investigates the differential expression of PD-L1 and alternative immune checkpoints (ICs; B7x, B7-H3, and HHLA2), and genetic alterations in PSCs. Tumor specimens of 41 PSC patients were evaluated. PD-L1, B7x, B7-H3, and HHLA2 were positive in 75.0%, 67.6%, 73.0%, and 91.9% of tumors, respectively. PD-L1 expression was significantly higher in the epithelial compared to the sarcomatoid component (median TPS: 50% vs. 0%,p= 0.010). Expression of PD-L1 in both components was only seen in 32.1% of patients. However, at least one IC was expressed in 92.9% of epithelial and 100% of sarcomatoid components. Furthermore,METex14 was detected in 19.5% of patients and was associated with a higher sarcomatoid percentage. Our preclinical studies revealed thatMETex14 induced PD-L1 expression via MAPK or PI3K/Akt pathways, and MET inhibitors decreased PD-L1 expression. Our findings demonstrate distinct expressions of ICs in PSC subcomponents. Thus, combination IC inhibition as a therapeutic strategy in PSC warrants further exploration. A high percentage ofMETex14 in PSC and its role in regulating PD-L1 expression reveal different therapeutic targets in this aggressive NSCLC subtype.