# Infiltration of TIM4-positive intratumoral macrophages serves as an adverse prognostic factor in breast cancer

## TL;DR

TIM4-positive macrophages in breast cancer tissues are linked to worse outcomes, suggesting they promote tumor growth.

## Contribution

TIM4 is identified as a novel marker for tumor-promoting macrophages in breast cancer.

## Key findings

- TIM4 is highly expressed in both carcinoma and stromal cells in breast cancer tissues.
- TIM4-positive stromal macrophages correlate with aggressive tumor traits and poor clinical outcomes.
- TIM4 does not co-localize with M1 or M2 macrophage markers, indicating a distinct macrophage subset.

## Abstract

T-cell immunoglobulin and mucin domain containing protein 4 (TIM4), a phosphatidylserine receptor primarily expressed on antigen-presenting cells, has been implicated in phagocytosis and immune regulation in various diseases, including malignancies. However, the significance of TIM4 in the breast cancer microenvironment remains unclear. In this study, we investigated the localization and clinical significance of TIM4 in breast cancer.

We immunolocalized TIM4 in human breast carcinoma tissues using immunohistochemistry (IHC) and multiplex fluorescence-immunohistochemistry (F-IHC) and examined its correlation with clinicopathological parameters and clinical outcomes.

TIM4 was highly expressed in both carcinoma cells and stromal cells in human breast carcinoma tissues. Multiplex F-IHC revealed that TIM4 was co-localized with CD68, a macrophage marker, whereas no co-localization was observed between TIM4 and CD80 (an M1 macrophage marker) or CD163 (an M2 macrophage marker). Prognostic analysis of 171 breast carcinoma tissues by IHC revealed that infiltration of TIM4-positive stromal cells was associated with an aggressive tumor phenotype, including increased proliferative and invasive potential, as well as poorer clinical outcomes. In contrast, TIM4 immunoreactivity in carcinoma cells showed no significant correlation with clinical outcomes.

These findings suggest that infiltration of TIM4-positive macrophages serves as a strong prognostic indicator in breast cancer and that TIM4 may represent a novel marker for tumor-promoting macrophages.

The online version contains supplementary material available at 10.1007/s12282-026-01825-8.