Soluble Tim-3 serves as a tumor prognostic marker and therapeutic target for CD8+ T cell exhaustion and anti-PD-1 resistance

Resistance to PD-1 blockade in onco-immunotherapy greatly limits its clinical application. T cell immunoglobulin and mucin domain containing-3 (Tim-3), a promising immune checkpoint target, is cleaved by ADAM10/17 to produce its soluble form (sTim-3) in humans, potentially becoming involved in anti-PD-1 resistance. Herein, serum sTim-3 upregulation was observed in non-small cell lung cancer (NSCLC) and various digestive tumors. Notably, serum sTim-3 is further upregulated in non-responding patients undergoing anti-PD-1 therapy for NSCLC and anti-PD-1-resistant cholangiocarcinoma patients. Furthermore, sTim-3 overexpression facilitates tumor progression and confers anti-PD-1 resistance in multiple tumor mouse models. Mechanistically, sTim-3 induces terminal T cell exhaustion and attenuates CD8 + T cell response to PD-1 blockade through carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1). Moreover, the ADAM10 inhibitor GI254023X, which blocks sTim-3 production, reduces tumor progression in Tim-3 humanized mice and reverses anti-PD-1 resistance in human tumor-infiltrating lymphocytes (TILs). Overall, human sTim-3 holds great predictive and therapeutic potential in onco-immunotherapy. • Patients with tumors resistant to anti-PD-1 therapy exhibit high serum sTim-3 levels • sTim-3 promotes tumor progression and confers anti-PD-1 resistance in tumor models • sTim-3 promotes CD8 + T cell exhaustion and resistance to PD-1 blockade through CEACAM-1 • The ADAM10 inhibitor suppresses tumor progression and reverses anti-PD-1 resistance Tim-3 is a promising immune checkpoint in tumor immunotherapy. Chen et al. demonstrate that soluble Tim-3 (sTim-3) is a potential marker of tumor prognosis and resistance to anti-PD-1 therapy. sTim-3 exacerbates CD8 + T cell exhaustion and inhibits response to anti-PD-1 treatment, suggesting sTim-3 as a target to enhance tumor immunotherapy.