Overcoming resistance to radiation is a great challenge in cancer therapy. Here, we highlight that targeting valosin‐containing protein (VCP) improves radiation sensitivity in esophageal squamous cell carcinoma (ESCC) cell lines and show the potential of using VCP as a prognosis marker in locally advanced ESCC treated with radiation therapy. Esophageal squamous cell carcinoma cell lines with high VCP expression were treated with VCP inhibitor combined with radiotherapy. Cell proliferation, colony formation, cell death, and endoplasmic reticulum (ER) stress signaling were evaluated. Moreover, patients with newly diagnosed locally advanced ESCC who were treated with radiotherapy were analyzed. Immunohistochemistry was used to detect the expression of VCP. The correlation between overall survival and VCP was investigated. Esophageal squamous cell carcinoma cells treated with VCP inhibitor and radiotherapy showed attenuated cell proliferation and colony formation and enhanced apoptosis. Further investigation showed this combined strategy activated the ER stress signaling involved in unfolded protein response, and inhibited the ER‐associated degradation (ERAD) pathway. Clinical analysis revealed a significant survival benefit in the low VCP expression group. Targeting VCP resulted in antitumor activity and enhanced the efficacy of radiation therapy in ESCC cells in vitro. Valosin‐containing protein is a promising and novel target. In patients with locally advanced ESCC who received radiotherapy, VCP can be considered as a useful prognostic indicator of overall survival. Valosin‐containing protein inhibitors could be developed for use as effective cancer therapies, in combination with radiation therapy.

As a metabolic mediator of antitumor immunity, indoleamine-2,3-dioxygenase 1 (IDO1) is upregulated in various types of cancer; however, the regulatory mechanism and clinical significance of IDO1 in non-small cell lung cancer (NSCLC) radiotherapy (RT) remain unclear. The present study investigated the role of IDO1 in the NSCLC microenvironment. MTT assay, immunofluorescence, apoptosis analysis, cell cycle analysis, and C57BL/6 and BALB/c nude mouse tumor models were utilized to evaluate the roles of the STAT5A/IDO1/kynurenine axis in radioresistance and in the immune microenvironment of NSCLC. Protein expression levels were evaluated by western blotting, immunofluorescence and immunohistochemistry. Flow cytometry was performed to assess the status of CD8 + T lymphocytes, regulatory T cells (Tregs) and immune-related inflammatory factors in C57BL/6 mice. Notably, IDO1 and STAT5A were positively associated with the immune microenvironment.RT treatment significantly promoted the expression levels of IDO1. IDO1 knockdown markedly enhanced the radiosensitivity of lung tumor cells and the anti-apoptotic properties of T lymphocytes. It was demonstrated that STAT5A knockdown suppressed T-cell apoptosis by inhibiting IDO1 enzyme function. Finally, in vivo experiments showed that STAT5A knockdown combined with RT was associated with greater numbers of CD8 + T cells and fewer Tregs. Results from the present study indicated that targeting the STAT5A/IDO1 axis may reshape the immune microenvironment and promote the efficacy of RT in NSCLC treatment. The present study may provide a theoretical foundation for more efficient use of immunotherapy regimens in NSCLC treatment.

BACKGROUND The advent of immune checkpoint inhibitors (ICIs) has revolutionized the management of several types of solid cancers, including lung cancer, by boosting the body's natural tumor killing response. However, it is undeniable that only a small proportion of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations can achieve long-term responses and benefit from immunotherapy. CASE SUMMARY Herein, we report the case of a 48-year-old man diagnosed with stage IV lung adenocarcinoma with an EGFR L858R mutation who was administered pembrolizumab monotherapy followed by pemetrexed and achieved a 10-month progression-free survival interval. In this case report, we show that ICIs were effective for our patient with EGFR-mutated NSCLC and discuss the characteristics of patients who can benefit from immunotherapy. CONCLUSION We suggest that patients with EGFR-mutated NSCLC with high PD-L1 expression (defined as ≥ 25%), the L858R mutation, smoking history, or pemetrexed pretreatment may benefit from immunotherapy.

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