TIM3+breast cancer cells license immune evasion during micrometastasis outbreak

Rozalén, C.; Sangrador, I.; Avalle, S.; Blasco-Benito, S.; Tzortzi, P.; Sanz-Flores, M.; ... ; Celia-Terrassa, T. (2025)

Article / Letter to editor

In metastasis, the dynamics of tumor-immune interactions during micrometastasis remain unclear. Identifying the vulnerabilities of micrometastases before outbreaking into macrometastases can reveal therapeutic opportunities for metastasis. Here, we report a function of T cell immunoglobulin and mucin domain 3 (TIM3) in tumor cells during micrometastasis using breast cancer (BC) metastasis mouse models. TIM3 is highly upregulated in micrometastases, promoting survival, stemness, and immune escape. TIM3+ tumor cells are specifically selected during early seeding of micrometastasis. Mechanistically, TIM3 increases beta-catenin/interleukin-1 beta (IL-1 beta) signaling, leading to stemness and immune-evasion by inducing immunosuppressive gamma delta T cells and reducing CD8 T cells during micrometastasis. Clinical data confirm increased TIM3+ tumor cells in BC metastasis and TIM3+ tumor cells as a biomarker of poor outcome in BC patients. (Neo)adjuvant TIM3 blockade reduces the metastatic seeding and incidence in preclinical models. These findings unveil a specific mechanism of micrometastasis immune-evasion and the potential use of TIM3 blockade for subclinical metastasis.

• All authors: Rozalén, C.; Sangrador, I.; Avalle, S.; Blasco-Benito, S.; Tzortzi, P.; Sanz-Flores, M.; Palomeque, J.A.; Torren-Duran, P.; Dalmau, M.; Brunel, H.; Coll-Manzano, A.; Perez-Núñez, I.; Martos, T.; Servitja, S.; Pérez-Buira, S.; Chacón, J.I.; Guerrero-Zotano, A.; Dueñas, E.M. de; Guillén, Y.; Comerma, L.; Bornejo, B.; Bigas, A.; Casanova-Acebes, M.; Alemany, A.; Rojo, F.; Albanell, J.; Celia-Terrassa, T.
• Date: 2025-08-11
• Journal: Cancer Cell
• Volume: 43
• Issue: 8
• Pages: 1549 - 1567.e9
• DOI: doi:10.1016/j.ccell.2025.06.015