TIM3 as a therapeutic target in anaplastic thyroid cancer: upregulation in M2-like macrophages induced by tumor microenvironment-derived TGFβ1

Abstract

Thyroid cancer (TC) is the most common endocrine malignancy. While papillary thyroid cancer (PTC) generally has a favorable prognosis, anaplastic thyroid cancer (ATC) is rare but highly aggressive, with limited treatment options, highlighting the urgent need for novel therapeutic targets. Macrophages are a major component of the immune infiltrate in TC, and their abundance is associated with poor prognosis. We recently identified upregulation of the immune checkpoint TIM3 (T-cell immunoglobulin and mucin-domain containing protein 3) on M2-like macrophages both in vitro and in ATC xenografts. In addition, we have shown that transforming growth factor β1 (TGFβ1) promotes macrophage polarization toward an M2-like phenotype. However, the role and clinical significance of TGFβ1 in regulating TIM3 expression in TC-associated macrophages remains unclear. We found that TGFβ1 secreted by ATC cells significantly increased HAVCR2 (TIM3) mRNA expression in human monocytes. Analysis of patient samples demonstrated elevated TIM3 expression in both PTC and ATC tissues compared with adenoma and normal thyroid counterparts. Analysis of publicly available single-cell RNA sequencing datasets further showed increased TIM3 expression in T cells from both tumor types. Notably, TIM3 upregulation was also localized to M2-like macrophages within the thyroid tumor microenvironment (TME), and positively correlated with TGFB1/CD163 expression, suggesting the involvement of a TGFβ–TIM3 axis in macrophages in TC. Combined targeting of the TIM3 and PD1 pathway in an immunocompetent mouse model of ATC led to a significant reduction in tumor growth. Together, these findings highlight TIM3 as a promising immunotherapeutic target in TC, with the potential to suppress macrophage-mediated pro-tumor activity while enhancing T-cell-driven anti-tumor immunity within the thyroid TME. © 2026 The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.