The combination of a PTP1B inhibitor, TNFR2 blocker, and PD‑1 antibody suppresses the progression of non‑small cell lung cancer tumors by enhancing immunocompetence.

Abstract

Lung cancer is increasingly recognized as a leading cause of cancer‑related mortality. Immunotherapy has emerged as a promising therapeutic approach for lung cancer, particularly non‑small cell lung cancer (NSCLC). Nonetheless, the response rate to programmed cell death 1 (PD‑1) inhibitors remains less than optimal. It has been suggested that protein tyrosine phosphatase 1B (PTP1B) plays a crucial role in the development and progression of cancer by facilitating T cell expansion and cytotoxicity. Our previous research demonstrated that the combination of tumor necrosis factor receptor 2 (TNFR2) with immune activity treatments synergistically suppresses tumor growth. This insight led to exploring the efficacy of a combined treatment strategy involving PD‑1 inhibitors, PTP1B inhibitors and TNFR2 antibodies (triple therapy) in NSCLC. In this context, the therapeutic effectiveness of these combination immunotherapies was validated in mouse models with NSCLC by analyzing the expansion and function of immune cells, thereby assessing their impact on tumor growth. The results indicated that inhibiting PTP1B decreases the expression of PD‑L1 and TNFR2 on LLC cells, along with an increase in the proportion of CD4⁺T and CD8⁺T cells. Compared with other treatment groups, the triple therapy significantly reduced tumor volume in mice with NSCLC and extended their survival. Moreover, this combination therapy altered the distribution of myeloid‑derived suppressor cells, dendritic cells, B cells and M1 macrophages, while increasing the proportion of CD8⁺T cells and reducing the proportion of Treg cells in the spleens, lymph nodes, and tumors of NSCLC models. The triple therapy also resulted in a decrease in PD‑L1, PTP1B and TNFR2 expression within NSCLC tumor tissues in mice. Overall, the triple therapy effectively suppressed tumor growth and improved outcomes in mice with NSCLC by modulating immune cell distribution and reducing levels of target immune proteins.