Thioredoxin: a key factor in cold tumor formation and a promising biomarker for immunotherapy resistance in NSCLC.

Immune checkpoint blockade (ICB) therapy has shown promising clinical efficacy in cancer treatment, but only a subset of patients experience significant therapeutic responses. Tumor cells respond to internal and external stresses, such as hypoxia and nutrient deprivation, by activating the unfolded protein response (UPR) in the tumor microenvironment. This response helps maintain homeostasis, promoting malignant progression, chemotherapy resistance, and immune escape. In this study, single-cell RNA sequencing (scRNA-seq) data from non-small cell lung cancer (NSCLC) patients treated with ICB revealed upregulation of thioredoxin (TXN) expression in the epithelial tissues of LUAD (lung adenocarcinoma) and LUSC (lung squamous cell carcinoma) patients with minimal pathological remission. High TXN expression was also associated with "cold tumors," characterized by a lack of T cells and low levels of chemokine receptors and immunomodulators. Experimental results showed that TXN was highly expressed in NSCLC tissues, and its knockdown significantly inhibited the proliferation and migration of A549 and SK-MES-1 cells. Furthermore, TXN knockdown enhanced T-cell-mediated cytotoxicity against these tumor cells, suggesting that TXN contributes to immune escape in NSCLC by promoting tumor cell proliferation and migration while inhibiting immune killing. Notably, TXN knockdown also upregulated CD40 expression, indicating that TXN may regulate immune escape in lung cancer through CD40 modulation.