# The Role of Cancer-Associated Fibroblasts and Tumor-Associated Macrophages in the Tumor Microenvironment and Their Impact on Ovarian Cancer Survival and Therapy

## TL;DR

This review explains how cancer-associated fibroblasts and tumor-associated macrophages in the tumor environment help ovarian cancer grow and resist treatment, and how targeting them could lead to better therapies.

## Contribution

The paper provides a comprehensive overview of CAFs and TAMs in ovarian cancer and highlights novel therapeutic strategies targeting these cells.

## Key findings

- CAFs and TAMs promote tumor growth, immune evasion, and therapy resistance through extracellular matrix remodeling and cytokine release.
- Targeting CAFs and TAMs via reprogramming or pathway inhibition shows promise for improving ovarian cancer treatment outcomes.
- Advances in single-cell sequencing and spatial transcriptomics allow for more precise targeting of CAF and TAM subtypes.

## Abstract

Ovarian cancer is one of the most lethal gynecologic malignancies due to its late diagnosis and resistance to conventional therapies. This review explores how two significant components of the tumor microenvironment, cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), contribute to ovarian cancer progression and treatment failure. We summarize how these cells promote tumor growth, immune evasion, and therapy resistance by remodeling the extracellular matrix and releasing pro-tumorigenic factors. We also highlight promising therapeutic strategies targeting CAFs and TAMs, including reprogramming approaches and pathway inhibitors. Understanding these mechanisms may guide future precision therapies and improve patient outcomes.

Ovarian cancer is the deadliest gynecologic cancer, mainly because it is often diagnosed late and resists standard treatments. The tumor microenvironment (TME) plays a major role in disease progression and therapy failure. Two key components of the TME, cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), create conditions that facilitate tumor growth and immune evasion. CAFs are highly diverse and originate from sources like fibroblasts and stem cells. They support cancer by remodeling the extracellular matrix, promoting angiogenesis, and releasing cytokines and growth factors that aid tumor survival. TAMs, which are usually in an M2 state, also promote metastasis and suppress immune responses by secreting immunosuppressive molecules. Together, CAFs and TAMs interact with cancer cells to activate pathways such as the TGF-β, IL-6, and PI3K/AKT pathways, which drive resistance to therapy. New treatments aim to block these interactions by targeting CAFs and TAMs through depletion, reprogramming, or pathway inhibition, often combined with immunotherapy. Advances such as single-cell sequencing and spatial transcriptomics now enable more precise identification of CAF and TAM subtypes, enabling more targeted therapies. This review summarizes their roles in epithelial ovarian cancer and explores how targeting these cells could improve outcomes.