一种B7家族蛋白的上调驱动治疗诱导的衰老癌细胞发生免疫逃逸

Background: Conventional cancer therapies, including ionizing radiation (IR) and chemotherapy, often drive tumor cells into a cellular senescence state. Accumulating evidence suggests that senescent tumor cells contribute to the establishment of an immunosuppressive tumor microenvironment (TME) and promote tumor recurrence. A B7 family protein, an immune checkpoint protein, is frequently overexpressed across various tumor types and is known to suppress T-cell activity, thereby facilitating immune evasion and resistance to immunotherapy. However, the molecular mechanisms underlying the role of this B7 family protein in therapy-induced senescent (TIS) cancer cells remain poorly understood. Methods: To elucidate the molecular mechanisms and immunoregulatory roles of the B7 family protein in TIS, we analyzed The Cancer Genome Atlas (TCGA) database to assess its expression across multiple cancer types. We further examined changes in its expression following IR or doxorubicin treatment in several human cancer cell lines, including A549 (lung), HCT116 wild-type (colon), HepG2 (liver), MIA PaCa-2 (pancreas), DU145 (prostate), and U2OS (bone). The role of the B7 family protein in cellular senescence was evaluated through gene knockdown experiments, and its impact on immune function was investigated using T cell-mediated cytotoxicity assays. Results: TCGA analysis revealed that the B7 family protein is highly expressed across diverse cancer types. Following IR or doxorubicin treatment, its expression was significantly upregulated in senescent cancer cells across multiple cell lines. Depletion of the B7 family protein did not alter the senescence phenotype, indicating that it is not directly involved in regulating cellular senescence. Mechanistically, its upregulation in IR-induced senescent cancer cells occurred predominantly at the transcriptional level rather than through post-transcriptional or post-translational mechanisms. Notably, depletion of the B7 family protein markedly enhanced T-cell infiltration and cytotoxic activity against senescent cancer cells, demonstrating that its upregulation impairs antitumor immunity in TIS. Conclusions: Our findings reveal the B7 family protein acts as a key regulator of immune suppression during therapy-induced senescence. This upregulation enables senescent cancer cells to evade T-cell mediated immune attack. Thus, inhibiting B7 family protein may offer a strategy to restore anti-improve immunity and improve therapeutic outcomes.