# Tumor–Immune Cell Crosstalk Drives Immune Cell Reprogramming Towards a Pro-Tumor Proliferative State Involving STAT3 Activation

## TL;DR

This study shows how breast cancer cells can reprogram immune cells to support tumor growth through a process involving a key protein called STAT3.

## Contribution

The study reveals that tumor-educated immune cells adopt a pro-tumor state driven by STAT3 activation, offering a new therapeutic target.

## Key findings

- Immune cells exposed to breast cancer cells show increased proliferation and activation of pro-tumor pathways.
- Blocking STAT3 reduces abnormal immune cell growth, suggesting a potential treatment strategy.
- Tumor exposure leads to elevated expression of pro-inflammatory cytokines like IL6 in immune cells.

## Abstract

Cancer can alter the behavior of immune cells to help tumors grow and spread. In this study, we explored how triple-negative breast cancer cells influence immune cells through direct contact and signals released by the tumor. We found that immune cells exposed to cancer cells become reprogrammed, showing increased growth and activation of pathways that support tumor progression. These changes were linked to a key signaling protein called STAT3. When STAT3 was blocked, the abnormal growth of monocytes was reduced, suggesting that targeting this pathway could help restore normal immune function. Our findings highlight how tumors manipulate immune cells towards a more pro-oncogenic phenotype and point to new strategies for improving cancer treatment by preventing immune cells from supporting tumor growth.

Background/Objectives: Tumor-induced immune reprogramming is increasingly recognized as a key mechanism by which cancers evade surveillance and promote disease progression. The interaction between cancer and immune cells within the tumor microenvironment (TME) can drive phenotypic and functional changes in immune populations, facilitating metastasis and immune evasion. Methods: In this study, we used co-culture models to expose THP1 monocytes to triple-negative breast cancer (TNBC) cells, MDA-MB-231 and BT-549, either directly or indirectly via tumor-conditioned media, to mimic tumor–immune cell communication. Transcriptomic and pathway analyses revealed that cancer-exposed monocytes adopt a reprogrammed phenotype marked by activation of pro-tumorigenic signaling pathways, enhanced proliferative capacity, and elevated expression of pro-inflammatory cytokines such as IL6. Results: Functional assays confirmed a significant increase in monocyte proliferation under both direct and indirect tumor exposure. Importantly, we demonstrated that this tumor-driven proliferation of THP1 cells could be suppressed by the STAT3 inhibitor STAT3-IN-12. This highlights the critical role of STAT3 signaling in mediating immune cell transformation and supporting a novel immunomodulatory approach for therapeutic intervention. Conclusions: These findings support the potential for targeting tumor-educated transcriptional programs as a novel immunomodulatory strategy in cancer treatment. Restoring immune cell homeostasis and suppressing pro-tumor phenotypes through pharmacological inhibition of the key signaling nodes such as STAT3 may complement existing cancer therapies. This study provides new insights into immune cell plasticity in cancer and identifies actionable strategies to counteract tumor-driven immune dysregulation.