Immune checkpoint blockade (ICB) therapy has achieved breakthroughs in the treatment of advanced non-small cell lung cancer (NSCLC). Nevertheless, the low response due to immuno-cold tumor microenvironment (TME) largely limits the application of ICB therapy. Based on the glycolytic/cholesterol synthesis axis, a stratification framework for EGFR wild-type NSCLC was developed to summarize the metabolic features of immuno-cold and immuno-hot tumors. The cholesterol subgroup displays the worst prognosis in immuno-cold NSCLC with significant enrichment of the cholesterol gene signature, indicating targeting cholesterol synthesis is essential for the therapy for immuno-cold NSCLC. Statin, the inhibitor for cholesterol synthesis, can suppress the aggressiveness of NSCLC in vitro and in vivo and also drastically reverse immuno-cold to an inflamed phenotype in vivo which exhibited a higher response to ICB therapy. Moreover, both our in-house data and meta-analysis further support that statin can significantly enhance ICB efficacy. In terms of preliminary mechanisms, statin could transcriptionally inhibit PD-L1 expression and induce ferroptosis in NSCLC cells. Overall, we reveal the significance of cholesterol synthesis in NSCLC and demonstrate the improved therapeutic efficacy of ICB in combination with statin.These findings could provide a innovative clinical insight to treat NSCLC patients with immuno-cold tumors.

Background Immune checkpoint blockade (ICB) only works well for a certain subset of patients with non-small cell lung cancer (NSCLC). Therefore, biomarkers for patient stratification are desired, which can suggest the most beneficial treatment. Methods In this study, three datasets (GSE126044, GSE135222, and GSE136961) of immunotherapy from the Gene Expression Omnibus (GEO) database were analyzed, and seven intersected candidates were extracted as potential biomarkers for ICB followed by validation with The Cancer Genome Atlas (TCGA) dataset and the in-house cohort data. Results Among these candidates, we found that human leukocyte antigen-DR alpha (HLA-DRA) was downregulated in NSCLC tissues and both tumor and immune cells expressed HLA-DRA. In addition, HLA-DRA was associated with an inflamed tumor microenvironment (TME) and could predict the response to ICB in NSCLC. Moreover, we validated the predictive value of HLA-DRA in immunotherapy using an in-house cohort. Furthermore, HLA-DRA was related to the features of inflamed TME in not only NSCLC but also in most cancer types. Conclusion Overall, HLA-DRA could be a promising biomarker for guiding ICB in NSCLC.

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Lung cancer has become the leading cause of cancer death all over the world. Nowadays, there is a consensus that the treatment of non-small cell lung cancer (NSCLC) prefers a combination of multidisciplinary comprehensive treatment and individualized treatment, which can significantly improve the prognosis of patients. Here, we report a female patient with recurrence-prone NSCLC. She had a decade-long disease course, during which the lesion recurred twice and finally cured with Multi-Disciplinary Treatment (MDT). An elderly female patient was admitted to the hospital after diagnosis of lung cancer, and treated with surgery and postoperative adjuvant chemotherapy. Five years later, suspicious lesions were found by computed tomography (CT) reexamination, and then confirmed tumor recurrence by puncture biopsy. Based on the genetic test results, gefitinib was used for subsequent targeted therapy, and the lesion gradually shrunk to disappear. However, the lesion appeared again two years later, after consultation the microwave ablation was adopted and the curative effect was excellent. At last, regular reexamination showed no abnormality, the patient has survived so far. The case proves the great benefit of multidisciplinary comprehensive treatment, especially microwave ablation for patient with recurrence-prone NSCLC. And the effect of systemic anti-tumor immune response induced by microwave ablation on lung cancer also needs to be further explored.