TIM3+ breast cancer cells license immune evasion during micrometastasis outbreak

• Published in: Cancer cell Vol. 43; no. 8; pp. 1549 - 1567.e9
• Main Authors: Rozalén, Catalina, Sangrador, Irene, Avalle, Silvia, Blasco-Benito, Sandra, Tzortzi, Panagiota, Sanz-Flores, María, Palomeque, José Ángel, Torren-Duran, Pau, Dalmau, Mariona, Brunel, Helena, Coll-Manzano, Albert, Pérez-Núñez, Iván, Martos, Tamara, Servitja, Sonia, Pérez-Buira, Sandra, Chacón, José Ignacio, Guerrero-Zotano, Ángel, Martínez de Dueñas, Eduardo, Guillén, Yolanda, Comerma, Laura, Bermejo, Begoña, Bigas, Anna, Casanova-Acebes, María, Alemany, Anna, Rojo, Federico, Albanell, Joan, Celià-Terrassa, Toni
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.08.2025
• Subjects: Animals; breast cancer; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; cancer immunoediting; Cell Line, Tumor; EMT; Female; Hepatitis A Virus Cellular Receptor 2 - genetics; Hepatitis A Virus Cellular Receptor 2 - immunology; Hepatitis A Virus Cellular Receptor 2 - metabolism; Humans; Immune Evasion; metastasis; Mice; micrometastasis; Neoplasm Micrometastasis - immunology; stemness; TIM3; TIM3 blockade; γδ T cells; immune-evasion; γδ T cells; metastasis; stemness; TIM3 blockade; breast cancer; micrometastasis; TIM3; EMT; cancer immunoediting
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2025.06.015

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 β-catenin/interleukin-1β (IL-1β) signaling, leading to stemness and immune-evasion by inducing immunosuppressive γδ 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. [Display omitted] •Immune pressure at distant organs selects TIM3+ tumor cells during micrometastasis•TIM3+ tumor cells exhibit stemness, EMT, and immune-evasive features•TIM3 in tumor cells is a biomarker of relapse and poor prognosis in BC patients•(Neo)adjuvant TIM3 blockade prevents metastatic seeding and metastasis initiation Rozalén et al. report that TIM3 in breast cancer drives a specific mechanism of immune escape during micrometastasis. TIM3+ tumor cells exhibit stemness/EMT features and promote immune-evasion by inducing immunosuppressive γδ T cells. TIM3 is a biomarker of poor outcome, and its blockade targets metastasis initiating cells during micrometastasis.