# Macrophages—Target and Tool in Tumor Treatment: Insights from Ovarian Cancer

## TL;DR

This paper reviews how macrophages in ovarian cancer can be both a target for treatment and a tool for delivering therapies, offering new hope for more effective cancer treatments.

## Contribution

The paper highlights the dual role of macrophages in ovarian cancer as both a target and a therapeutic tool, emphasizing novel strategies like CAR-Ms and MDCs.

## Key findings

- Macrophages can be reprogrammed or depleted to inhibit cancer progression and resistance.
- Macrophage–Drug Conjugates (MDCs) use iron-binding protein transfer for targeted drug delivery.
- Chimeric Antigen Receptor Macrophages (CAR-Ms) are being developed to enhance anti-tumor immunity.

## Abstract

Ovarian cancer is a highly aggressive malignancy with significant treatment challenges, especially given the limited success of current treatments. Our investigation highlights that macrophages, which are abundant within tumors, frequently drive cancer progression and resistance to therapy, but they can also be reprogrammed to exert anti-tumor effects or utilized as anti-cancer agents in novel immunotherapies. In this review, we focus on the dual therapeutic potential of macrophages—as both a target and a tool. As a target, strategies include inhibiting their recruitment, selectively depleting tumor-associated macrophages (TAMs), or reprogramming them toward tumoricidal phenotypes. As a tool, macrophages are being engineered into Chimeric Antigen Receptor Macrophages (CAR-Ms) or employed as delivery vehicles for anti-cancer agents. A particularly promising innovation is the development of Macrophage–Drug Conjugates (MDCs), which exploit the transfer of iron-binding proteins (TRAIN) mechanism for precise intracellular drug delivery. These macrophage-based approaches hold significant promise for advancing more effective treatments for ovarian cancer and other solid tumors.

Today, science and medicine are striving to develop novel techniques for treating deadly diseases, including a wide range of cancers. Efforts are being made to better understand the molecular and biochemical mechanisms of tumor cell functioning, but a particular emphasis has recently been given to investigating immune cells residing in the tumor microenvironment, which may lead to revolutionary benefits in the design of new immunotherapies. Among these cells, tumor-associated macrophages (TAMs) are highly abundant and act as critical regulators of ovarian cancer progression, metastasis, and resistance to therapy. Their dual nature—as drivers of malignancy and as potential therapeutic mediators—has positioned them at the forefront of research into next-generation immunotherapies. As therapeutic targets, approaches include blocking macrophage recruitment (e.g., CSF-1/CSF-1R inhibitors), selectively depleting subsets of TAMs (e.g., via Folate Receptor Beta), or reprogramming immunosuppressive M2-like macrophages toward an anti-tumor M1 phenotype. On the other hand, macrophages can also serve as a therapeutic tool—they may be engineered to enhance anti-tumor immunity, as exemplified by the development of Chimeric Antigen Receptor Macrophages (CAR-Ms), or leveraged as delivery vehicles for targeted drug transport into the tumor microenvironment. A particularly innovative strategy involves Macrophage–Drug Conjugates (MDCs), which employs the transfer of iron-binding proteins (TRAIN) mechanism for precise intracellular delivery of therapeutic agents, thereby enhancing drug efficacy while minimizing systemic toxicity. This review integrates current knowledge of TAM biology, highlights emerging therapeutic approaches, and underscores the promise of macrophage-based interventions in ovarian cancer. By integrating macrophage-targeting strategies with advanced immunotherapeutic platforms, novel treatment paradigms may be determined that could substantially improve outcomes for patients with ovarian cancer and other solid tumors. Our work highlights that macrophages should be a particular area of research interest in the context of cancer treatment.