It has been widely acknowledged that the use of immune checkpoint inhibitors (ICI) is an effective therapeutic treatment in many late-stage cancers. However, not all patients could benefit from ICI therapy. Several biomarkers, such as high expression of PD-L1, high mutational burden, and higher number of tumor infiltration lymphocytes have shown to predict clinical benefit from immune checkpoint therapies. One approach using ICI in combination with other immunotherapies and targeted therapies is now being investigated to enhance the efficacy of ICI alone. In this review, we summarized the use of other promising immunotherapies and targeted therapies in combination with ICI in treatment of lung cancers. The results from multiple animals and clinical trials were reviewed. We also briefly discussed the possible outlooks for future treatment.

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, and its demarcation contributes to various therapeutic outcomes. However, a small subset of tumors shows different molecular features that are in contradiction with pathological classification. Unsupervised clustering was performed to subtype NSCLC using the transcriptome data from the TCGA database. Next, immune microenvironment features of lung adenocarcinoma (LUAD), lung squamous carcinoma (LUSC), and lung adenoid squamous carcinoma (LASC) were characterized. In addition, diagnostic biomarkers to demarcate LASC among LUSC were screened using weighted gene co-expression network analysis (WGCNA) and validated by the in-house cohort. LASC was identified as a novel subtype with adenoid transcriptomic features in LUSC, which exhibited the most immuno-escaped phenotype among all NSCLC subtypes. In addition, FOLR1 was identified as a biomarker for LASC discrimination using the WGCNA analysis, and its diagnostic value was validated by the in-house cohort. Moreover, FOLR1 was related to immuno-escaped tumors in LUSC but not in LUAD. Overall, we proposed a novel typing strategy in NSCLC and identified FOLR1 as a biomarker for LASC discrimination.