# Turning the Body's Immune Cells Back Against Ovarian Cancer: New Ways to Target Tumor-Associated Macrophages Ovarian cancer is the deadliest gynecologic cancer, and one major reason is that the immune cells around the tumor, called tumor-associated macrophages (TAMs), often switch sides and help the cancer grow. This review explains how TAMs are recruited, how they help cancer spread and resist chemotherapy, and reviews the newest treatment strategies being tested to eliminate them, block their recruitment, or re-program them to fight cancer instead. The authors conclude that while most TAM-targeted therapies are still in early-stage trials, a deeper understanding of these cells could lead to smarter, biomarker-guided treatments for patients with ovarian cancer. # Turning the Body's Immune Cells Back Against Ovarian Cancer: New Ways to Target Tumor-Associated Macrophages ## Table of Contents - Key Points - Why This Research Matters - Where Do Tumor-Associated Macrophages Come From? - How TAMs Help Ovarian Cancer Spread - How TAMs Cause Chemotherapy Resistance - Strategy 1: Depleting TAMs - Strategy 2: Blocking TAM Recruitment - Strategy 3: Restoring the "Eat Me" Signal (Phagocytosis) - Strategy 4: Converting M2 Macrophages Back to M1 - Strategy 5: Preventing M2 Polarization - Strategy 6: Correcting the Tumor Environment's Cues - Clinical Implications: What This Means for Patients - Limitations of Current Research - Recommendations for the Future - Frequently Asked Questions - Source Information ## Key Points - In ovarian cancer, tumor-associated macrophages are the most abundant immune cells and mostly exist in an immunosuppressive M2 state that promotes growth, spread and drug resistance. - Mirvetuximab soravtansine, targeting FRα on tumor cells, is approved for FRα-positive, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer after one to three prior regimens. - Most TAM-targeted strategies — depletion, recruitment blockade, phagocytosis restoration, reprogramming and polarization inhibition — remain in early-phase trials without definitive clinical validation. - On-target toxicity is a concern because macrophages also perform essential immune functions elsewhere in the body, and not all patients respond identically given tumor heterogeneity. - The authors recommend single-cell and spatial transcriptomics, humanized models, rational combination therapies and biomarker-guided trials to move TAM-directed treatments toward clinical use. ## Why This Research Matters Ovarian cancer is the most lethal gynecologic malignancy worldwide. Its aggressive behavior is shaped by the tumor microenvironment (TME) — the dynamic ecosystem surrounding the tumor. This ecosystem contains not only malignant cells, but also fat cells, blood vessels, connective-tissue fibroblasts, immune lymphocytes, dendritic cells, and cancer-associated fibroblasts. Through constant two-way communication with these cellular and non-cellular components, tumor cells act as adaptive entities. They integrate signals from the immune, endocrine, and nervous systems to build a self-sustaining niche that promotes cancer formation, metastasis, and treatment resistance. The ovarian cancer microenvironment is notably immunosuppressive, meaning it actively suppresses the immune system's ability to attack the tumor. Among all immune cells infiltrating ovarian cancer, macrophages are the most abundant population. These cells contribute to multiple hallmarks of malignancy, including helping tumor cells enter the bloodstream and suppressing anti-tumor immunity. Fibroblasts also play a critical role, supporting migration of tumor cells from the primary site, aiding systemic spread, and guiding blood vessel cells during tumor angiogenesis (new blood vessel formation). **The key message:** TAMs are central mediators of the crosstalk between tumor cells and the microenvironment. In ovarian cancer, TAMs predominantly exist in an immunosuppressive "M2" state that promotes tumor growth, invasion, blood vessel formation, immune evasion, and the ability to spread. For these reasons, TAMs have emerged as a key target for therapy. ## Where Do Tumor-Associated Macrophages Come From? Scientists once believed that macrophages arose exclusively from circulating monocytes (a type of white blood cell produced in the bone marrow). Lineage-tracing studies have challenged this view. They reveal that while many macrophages do originate from bone marrow and spleen progenitors, a considerable proportion are established during embryonic development and persist as self-renewing tissue-resident macrophages (TRMs). During development, macrophages derived from the yolk sac and fetal liver seed peripheral tissues. They are later joined by bone marrow–derived monocytes in response to injury, infection, or inflammation. These insights have reshaped the traditional M1/M2 polarization paradigm. For instance, TAMs expressing CD163 or CD206 — markers typically associated with the tumor-promoting M2 phenotype — can actually exhibit M1-like, T cell–activating properties in gastrointestinal cancers and ovarian cancer ascites (fluid build-up in the abdomen). This means the simple M1/M2 dichotomy oversimplifies the true functional continuum of macrophages in the tumor environment. High-dimensional analyses, including single-cell RNA sequencing (a technique that reads the genetic activity of individual cells), have revealed remarkable heterogeneity that goes beyond classical classifications. In tumors, most TAMs show M2-like features, while a minority display M1-like traits that can contribute to tumor initiation, blood vessel formation, and metastasis. Human tissue-resident macrophages lack definitive lineage markers, so their developmental origins and specialized roles remain poorly characterized. The authors stress an urgent need to clarify macrophage heterogeneity and lineage diversity in human tumors to advance precision immunotherapy. ## How TAMs Help Ovarian Cancer Spread TAMs are the predominant immune cell population in the ovarian tumor environment and are critical drivers of tumor progression and metastatic spread. They help tumor cells proliferate, invade, and establish peritoneal metastases (secondary tumors in the abdominal cavity) — processes closely linked to malignant ascites. Within ascitic fluid, tumor cells frequently aggregate into multicellular spheroids (clusters) that adhere to the peritoneal mesothelium (the membrane lining the abdomen), initiating secondary lesions. In one study highlighted by the authors, highly metastatic ovarian cancer cells injected into mice produced persistent peritoneal dissemination, whereas non-metastatic cell lines failed to spread. What drives this difference? Mechanistically, β-catenin signaling, which underpins tumor growth and invasion, plays a key role. Silencing β-catenin reduces omental metastases (spread to the abdominal fat tissue) and metastatic nodules. This is accompanied by depletion of CD68+ and CD163+ TAMs (two markers of immunosuppressive macrophages). β-catenin activation in tumor cells upregulates EMT-promoting transcription factors such as ZEB1 and Snail, along with chemokines (chemical attractants) including CCL2 and CCL3. These chemokines recruit monocytes and polarize them into M2-like TAMs. In a positive feedback loop, these recruited TAMs secrete high levels of CCL2 and IL-6, which act on tumor cells via CCR2 and IL-6R receptors respectively. IL-6 binding activates the JAK/STAT3 pathway, driving expression of EMT-related genes and enhancing tumor motility. Meanwhile, CCL2–CCR2 signaling stimulates NF-κB activity, which synergizes with β-catenin to reinforce EMT programs. **In plain terms:** The tumor sends signals to recruit macrophages, the macrophages respond by sending signals back that make the tumor more invasive, and this vicious cycle accelerates migration, invasion, and metastasis. ## How TAMs Cause Chemotherapy Resistance Standard treatment for ovarian cancer is cytoreductive surgery followed by platinum-based chemotherapy (drugs such as cisplatin and carboplatin). However, resistance to platinum compounds — whether present from the start (intrinsic) or developed over time (acquired) — remains a central challenge. It is often driven by pre-existing resistant tumor cell clones or by selective pressure from repeated treatments. Accumulating evidence implicates the tumor microenvironment as a major contributor to relapse and drug resistance. TAMs, in particular, are linked to chemoresistance. Although this was initially characterized in breast cancer, TAM-driven resistance is increasingly recognized in ovarian cancer. Notably, the M2-polarized subset of TAMs is closely associated with tumor progression, immune evasion, and drug resistance. One study found elevated blood levels of a circular RNA called circITGB6 in patients with platinum-resistant ovarian cancer compared to platinum-sensitive cases. This finding was accompanied by an expansion of M2 macrophages, suggesting that circITGB6-driven M2 polarization is a mechanism of resistance. In another study, co-culturing ovarian cancer cells with macrophages reduced carboplatin sensitivity in a dose-dependent manner, coinciding with a shift toward the M2-like phenotype. Macrophages communicate with tumor cells through exosomes (tiny membrane-bound particles that carry messages, including genetic material). Hypoxic (low-oxygen) ovarian cancer cells recruit macrophages and polarize them into a TAM-like phenotype. These TAMs then release exosomes containing miR-223, a microRNA that confers chemoresistance both in the lab and in living animals through the PTEN–PI3K/AKT pathway, a well-known cell-survival signaling chain. Emerging evidence supports the therapeutic potential of blocking exosome secretion to counter TAM-mediated chemoresistance. For example, a pharmacological inhibitor called GW4869 blocks neutral sphingomyelinase, an enzyme needed for exosome production. GW4869 has been shown to reduce exosomal miR-223 levels, restore PTEN expression, and enhance cisplatin sensitivity in ovarian cancer cells co-cultured with TAMs. In living mice, GW4869 attenuated tumor growth and enhanced chemotherapy effectiveness. ## Strategy 1: Depleting TAMs The first therapeutic approach is to physically remove TAMs from the tumor. Here, the folate receptor beta (FRβ) is a promising target. FRβ is specifically overexpressed on M2-polarized TAMs in various epithelial malignancies, including ovarian cancer. Unlike folate receptor alpha (FRα), which is mainly expressed on tumor cells themselves, FRβ localizes predominantly on immune cells within the tumor environment — particularly immunosuppressive macrophages. In syngeneic mouse models (mice with intact immune systems bearing tumors from the same genetic background), chimeric antigen receptor (CAR) T cells — immune cells engineered to recognize a specific target — were designed to recognize FRβ. These CAR T cells selectively eradicated FRβ+ TAMs. This approach effectively reshaped the immunosuppressive tumor environment into a pro-inflammatory one, enhancing monocyte influx, recruiting endogenous CD8+ T cells (the immune system's "killer" cells), delaying tumor progression, and prolonging survival. Rodriguez-Garcia and colleagues demonstrated that this FRβ CAR-T treatment caused transient weight loss but achieved specific depletion of FRβ+ TAMs and conferred a significant survival advantage. This suggests that removing the "bad" macrophages can unleash the body's own immune response against the tumor. In contrast, FRα is overexpressed directly on tumor cells in epithelial ovarian cancer. This expression pattern has enabled the development of antibody–drug conjugates (ADCs) — a "smart bomb" therapy where a targeting antibody delivers a toxic drug directly to cancer cells. Mirvetuximab soravtansine (MIRV) is an FRα-targeting ADC with demonstrated clinical efficacy in platinum-resistant epithelial ovarian cancer. In the phase II SORAYA trial, MIRV was evaluated in patients with FRα-high, platinum-resistant disease who had previously been treated with bevacizumab. Of note, 48% (about 1 in 2) had received 3 or more prior lines of therapy, and 13% had previously taken PARP inhibitors (a class of targeted drugs). MIRV monotherapy produced a high objective response rate (ORR, the proportion of patients whose tumors shrank or disappeared) with durable responses and a favorable safety profile, regardless of prior therapies. Subsequently, in a phase III trial, Moore and colleagues compared MIRV to standard chemotherapy. They reported lower rates of grade ≥3 adverse events (severe side effects), fewer dose reductions, and fewer treatment discontinuations with MIRV. In patients with high FRα expression, MIRV surpassed chemotherapy on secondary endpoints, showing a higher ORR, greater CA125 responses (CA125 is a blood marker used to track ovarian cancer), and improved patient-reported outcomes — although progression-free survival did not differ significantly between the groups. MIRV is now approved for FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancers after one to three prior treatment regimens. The ADC field is expanding rapidly, with more than 20 ongoing trials across gynecologic malignancies, including a phase III trial (NCT04296890) of MIRV in FRα-high platinum-resistant ovarian cancer. ## Strategy 2: Blocking TAM Recruitment Instead of killing TAMs after they arrive, a second strategy aims to stop them from entering the tumor in the first place. A key player here is periostin (POSTN), a secreted matricellular protein (a protein that helps organize the structural scaffold around cells). POSTN is implicated in tumor progression and poor prognosis across many cancers, including ovarian cancer. POSTN overexpression enhances migration, chemoresistance, and macrophage recruitment. When Tang and colleagues silenced POSTN using siRNA (a tool that silences specific genes) in A2780 ovarian cancer cells, the ability of those cells to attract macrophages was markedly diminished. Similarly, Zeng and colleagues showed that removing POSTN suppressed macrophage migration, while adding POSTN back restored monocyte invasion. POSTN strongly attracts macrophages and drives M2 polarization, identifying it as both a prognostic biomarker and a therapeutic target. Lin and colleagues reported that POSTN enrichment in invasive ovarian cancer correlates with increased migration, invasion, and metastasis, whereas knockdown of POSTN reduced tumor growth in living animals. Mechanistically, POSTN activates integrin–FAK/NF-κB signaling, which induces inflammatory cytokines (MIP-1β, MCP-1, TNF-α, RANTES), thereby enhancing monocyte chemotaxis (attraction) and M2 polarization. Notably, metastases from POSTN-overexpressing SKOV3 ovarian cancer cells were enriched in cancer-associated fibroblasts (CAFs). A protein called DDR2 on CAFs regulates POSTN via ITGB1 to activate PI3K/AKT and Src pathways. Additionally, a long non-coding RNA called LINC00520 upregulates POSTN by "sponging up" miR-577, triggering ILK/Akt/mTOR activation. Blocking this with POSTN knockdown or the ILK/Akt/mTOR inhibitor OSU-T315 abrogates these effects. Interestingly, POSTN also has effects outside of cancer — POSTN deficiency worsens alcohol-associated liver disease in mice, while restoring hepatic POSTN is protective. Despite its central role in ovarian cancer, the authors emphasize that **no clinical study has yet targeted POSTN directly**. ## Strategy 3: Restoring the "Eat Me" Signal (Phagocytosis) Macrophages are naturally equipped to engulf and destroy abnormal cells — a process called phagocytosis. But tumor cells exploit a "don't eat me" signal to avoid this fate. The signal comes from CD47, a glycoprotein widely expressed on tumor cells, which transmits its message by interacting with signal regulatory protein alpha (SIRPα) on macrophages. Blocking the CD47–SIRPα interaction restores the macrophages' phagocytic activity and has emerged as a key immunotherapy strategy. Therapeutic candidates include anti-CD47 monoclonal antibodies (lab-made proteins that bind to a specific target) such as Hu5F9-G4 and CC-90002, as well as SIRPα–Fc fusion proteins such as TTI-621 and ALX148. In a phase Ib trial (NCT02953782), Hu5F9-G4 combined with cetuximab (an antibody targeting the EGFR receptor) produced encouraging responses in advanced solid tumors, including late-stage ovarian cancer. In Sézary syndrome (a rare type of cutaneous T-cell lymphoma), CD47 expression is upregulated by the immune signaling molecule interleukin 4 (IL-4). Blocking CD47–SIRPα with the decoy receptor TTI-621 enhanced macrophage phagocytosis and reduced tumor burden. A phase I trial reported by Ansell and colleagues confirmed the safety and clinical responses of TTI-621 monotherapy in various blood cancers, including B- and T-cell lymphomas. Mechanistically, TTI-621 does more than enhance macrophage function. It also boosts CD8+ T cell cytotoxicity and promotes M1 polarization when combined with anti-PD-L1 therapy (checkpoint inhibitors that remove the brakes on immune cells), effectively suppressing lymphoma growth in laboratory experiments. Beyond enhancing phagocytosis, ALX148 activates dendritic cells (immune cells that present antigens to T cells) and reprograms TAMs toward an inflammatory phenotype, stimulating innate anti-tumor immunity. Evorpacept (also known as ALX78) is a next-generation fusion protein consisting of a modified SIRPα D1 domain linked to an inactive human IgG1 Fc fragment. Notably, it has roughly half the molecular weight of a conventional antibody, which may improve tumor penetration. Lakhani and colleagues demonstrated that evorpacept is hematologically safe (does not harm blood cells, a common concern with CD47 blockers because red blood cells also carry CD47). In preclinical models, it synergized with anti–PD-1/PD-L1 antibodies to enhance phagocytosis, pro-inflammatory polarization, dendritic cell activation, and cytotoxic immune responses. A phase II study (NCT05467670) is currently testing ALX148 in combination with liposomal doxorubicin (a form of chemotherapy) and pembrolizumab (a PD-1 checkpoint inhibitor) in platinum-resistant ovarian cancer. A novel agent called ligufalimab (AK117), a humanized IgG4 anti-CD47 antibody, binds CD47 with high affinity while avoiding hemagglutination (clumping of red blood cells) — an important safety advantage. ## Strategy 4: Converting M2 Macrophages Back to M1 Rather than eliminating TAMs, a fourth strategy tries to convert the tumor-promoting M2 macrophages back into the anti-tumor M1 type. One promising tool is a class of drugs called bromodomain and extraterminal domain inhibitors (BET inhibitors, or BETi). These drugs regulate epigenetic transcription — meaning they control which genes are switched on or off without changing the DNA sequence itself. In ovarian cancer, Wilson and colleagues reported that the BET inhibitor INCB054329 impairs homologous recombination (a DNA repair process) and augments the efficacy of poly(ADP-ribose) polymerase inhibitors (PARP inhibitors). PARP inhibitors are an important targeted therapy for ovarian cancer, but their clinical benefit is limited by resistance and toxicity, so combining them with BET inhibitors may help. Novel delivery platforms are also being explored. In ovarian and breast cancer models, Juan and colleagues showed that JQ1-loaded nanocarriers (tiny drug-delivery particles) enhanced anti-proliferative effects and synergized with olaparib (a PARP inhibitor). Villar-Prados and colleagues demonstrated that BET inhibition suppresses Notch3 signaling (a pathway involved in cell growth) and reduces tumor growth in its natural location within the body. One BET inhibitor, ZEN-3694, is currently under clinical evaluation in combination regimens for solid tumors, including recurrent ovarian cancer, across multiple trials (NCT05422794, NCT05327010, NCT03901469, NCT04986423, NCT04471974, NCT05071937). Beyond direct anti-tumor effects, recent evidence shows BET inhibitors also modulate the tumor immune environment by reprogramming TAMs. BET inhibition downregulates M2-polarizing transcription factors such as IRF4 and STAT6, while simultaneously enhancing NF-κB–dependent pro-inflammatory gene expression. This promotes a phenotypic switch from immunosuppressive M2 macrophages to anti-tumor M1 macrophages. The reprogramming leads to increased secretion of cytokines like IL-12 and TNF-α, enhanced antigen presentation (displaying tumor pieces to immune cells for attack), and improved recruitment of cytotoxic T cells. In breast and ovarian cancer models, JQ1 treatment reduced macrophage infiltration and upregulated MHC II and iNOS expression in macrophages — both markers of M1 polarization. This fosters an "inflamed" tumor environment conducive to immune-mediated tumor clearance. Additionally, BET inhibitor-mediated epigenetic remodeling suppresses immune checkpoint molecules such as PD-L1 on both tumor cells and TAMs, potentially enhancing the effectiveness of checkpoint inhibitor therapies. **The dual effect is notable:** BET inhibitors act both as direct anti-cancer agents and as immunomodulators, simultaneously hitting the tumor and reshaping the immune environment. In parallel, researchers are exploring M1 macrophage-derived extracellular vesicles (M1 MEVs) — tiny particles released by M1 macrophages that carry reprogramming messages. Schweer and colleagues demonstrated that human M1 MEVs robustly induce M2-to-M1 repolarization, both in isolated macrophages and in co-culture with ovarian cancer cells. They can even target tumor xenografts (human tumors grown in mice), although clinical translation remains unproven. ## Strategy 5: Preventing M2 Polarization A fifth strategy attacks the process that creates M2 TAMs in the first place. M2-polarized TAMs, as the dominant immune components of the tumor environment, critically drive migration, invasion, immune evasion, and treatment resistance in ovarian cancer. A key molecule here is CTHRC1 (collagen triple helix repeat containing 1). In epithelial ovarian cancer, overexpression of CTHRC1 promotes EMT, enhancing tumor invasion and metastasis. This same mechanism is implicated in lung, gastrointestinal, breast, and pancreatic cancers. Ovarian cancer cells secrete CTHRC1, which activates STAT6 signaling in TAMs, inducing their M2 polarization. These M2 TAMs then further stimulate tumor migration and invasion, forming a positive feedback loop. **Silencing CTHRC1 abrogates STAT6-mediated M2 polarization, suppresses metastasis, and delays disease progression**, highlighting CTHRC1 as a potential therapeutic target. Another player is miR-30b-3p, a microRNA that is downregulated in ovarian cancer R3 cells. When overexpressed, it suppresses proliferation, promotes apoptosis (programmed cell death), slows cell cycle progression, and inhibits migration and invasion. It directly targets CTHRC1, linking it to EMT. This suggests miR-30b-3p could serve as both a biomarker and a therapeutic candidate. Circular RNAs (circRNAs) add another regulatory layer. CircITGB6 interacts with two partners, IGF2BP2 and FGF9 mRNA, to stabilize FGF9 transcripts, induce M2 polarization, and confer cisplatin resistance. Combining cisplatin with an antisense oligonucleotide (ASO) — a short synthetic strand designed to bind and disable circITGB6 — markedly suppressed tumor growth and improved survival in experimental models. ## Strategy 6: Correcting the Tumor Environment's Cues The sixth approach recognizes that the tumor environment itself sends the signals that corrupt macrophages. Hypoxia (low oxygen), a hallmark of solid tumors, profoundly shapes ovarian cancer progression. In ascitic fluid, exosomal miR-940 is transferred to macrophages, reprogramming them toward an M2 phenotype that promotes ovarian cancer cell proliferation and migration. Thus, miR-940 functions as a tumor-promoting regulator through TAM polarization. In parallel, hypoxic stress elevates levels of several other microRNAs — miR-21-3p, miR-125b-5p, and miR-181d-5p — in ovarian cancer–derived exosomes. When macrophages take up these vesicles (via mechanisms mediated by HIF-1α and HIF-2α, the master regulators of the low-oxygen response), they adopt TAM-like phenotypes that further enhance tumor growth and metastatic potential. Inhibiting miR-223 partially attenuates TAM-derived exosome–induced chemoresistance. This indicates that additional exosomal cargo — including proteins and other microRNAs — also contributes to drug resistance. Among these, the miR-223/PTEN/PI3K/AKT axis has been identified as a major driver of chemoresistance in ovarian cancer cells, underscoring exosomes as potential therapeutic targets to restore chemosensitivity. Other microRNA circuitry is also being mapped. Recent findings show that circ-BNC2 inhibits ovarian cancer progression via the miR-223-3p/FBXW7 axis. FBXW7 is a recognized tumor suppressor. In oral squamous cell carcinoma, FBXW7 inhibits EMT through PI3K/AKT signaling; in colorectal cancer, it regulates proliferation and apoptosis via the Notch and Akt/mTOR pathways. In ovarian cancer, FBXW7 expression is reduced and inversely associated with miR-223-3p, while positively correlating with circ-BNC2. Functionally, FBXW7 suppresses invasion and migration. A similar regulatory axis, circ-BNC4/miR-223-3p/LARP3, was identified with comparable implications. ## Clinical Implications: What This Means for Patients These findings matter for patients because they point toward new treatment options for a cancer that desperately needs them. Ovarian cancer's immunosuppressive tumor environment fosters immune evasion, metastasis, and chemoresistance, and M2-polarized TAMs sit at the center of all three problems. The therapeutic strategies described in this review fall into five broad categories: - **Depletion:** Using CAR T cells or antibody-drug conjugates to eliminate TAMs (targeting FRβ) or kill tumor cells directly (targeting FRα, as with the approved drug mirvetuximab soravtansine) - **Recruitment blockade:** Preventing macrophages from entering the tumor by targeting attractant proteins like periostin (POSTN) - **Phagocytosis restoration:** Blocking the CD47–SIRPα "don't eat me" signal so macrophages can engulf tumor cells again — approaches include magrolimab (Hu5F9-G4), TTI-621, evorpacept (ALX148), and ligufalimab (AK117) - **Reprogramming:** Converting M2 macrophages back to the cancer-fighting M1 type using BET inhibitors or M1-derived extracellular vesicles - **Polarization inhibition:** Interrupting the signals (CTHRC1, exosomal microRNAs like miR-223 and miR-940) that create and maintain M2 TAMs For patients with platinum-resistant ovarian cancer — a particularly difficult situation — the approval of mirvetuximab soravtansine represents a concrete advance, offering a targeted option that can be less toxic than standard chemotherapy while still producing meaningful tumor responses. The authors caution, however, that most TAM-targeted therapies are still in early-phase trials without definitive clinical validation. On-target toxicity — meaning side effects caused by the therapy hitting similar cells elsewhere in the body — remains a real concern, as does the challenge that not all patients will respond identically given the heterogeneity of their tumors and immune environments. ## Limitations of Current Research The authors identify several translational barriers that stand between laboratory promise and clinical reality: - **TAM heterogeneity:** Tumor-associated macrophages are not one uniform cell type. The simple M1/M2 classification fails to capture the true diversity revealed by single-cell analyses. - **Lack of specific markers:** Scientists lack reliable markers that uniquely identify pro-tumoral TAM subsets in humans, making it hard to target them precisely. - **Incomplete understanding of macrophage origins in humans:** While mouse studies have traced macrophage development carefully, human tissue-resident macrophages lack definitive lineage markers, leaving their origins and roles insufficiently characterized. - **Potential on-target toxicity:** Depleting or reprogramming macrophages may have unintended consequences, since macrophages also perform essential immune functions throughout the body. - **Early-stage evidence:** Most TAM-targeted therapies remain in phase I or II trials, and some approaches (like targeting POSTN) have not yet reached clinical testing at all. - **Preclinical nature of much evidence:** Many mechanistic findings — such as the role of exosomal miR-223 in chemoresistance — come from cell cultures and mouse models, which do not always predict human responses. ## Recommendations for the Future To bridge these gaps, the authors recommend a clear research agenda. Future studies should employ single-cell and spatial transcriptomics — techniques that reveal which genes are active in individual cells and where those cells are located within the tumor — to define TAM subsets with precision. They also call for the development of humanized models (animal models engineered to carry human immune cells or tissues) that more faithfully recapitulate the human tumor environment. This would improve the odds that preclinical successes translate to bedside benefits. Rational combination therapies will also be essential. Because TAMs interact with so many other components of the immune system, combining TAM-targeted agents with checkpoint inhibitors, chemotherapy, or PARP inhibitors may produce synergistic effects. For example, BET inhibitors suppress PD-L1 on both tumor cells and TAMs, potentially priming tumors to respond better to PD-1/PD-L1 checkpoint blockade. Finally, biomarker-guided clinical trials are essential to optimize patient selection and therapeutic efficacy. Just as mirvetuximab soravtansine was approved specifically for patients with high FRα expression, future TAM-directed therapies will likely need companion biomarkers to identify which patients are most likely to benefit. In summary, the authors conclude that a deeper mechanistic understanding of TAM plasticity and intercellular networks will be key to advancing TAM-directed interventions toward clinical translation in ovarian cancer. For patients, this research agenda offers hope that the very immune cells currently helping the tumor could one day be converted into powerful allies against it. ## Frequently Asked Questions ### What are tumor-associated macrophages and why do they matter in ovarian cancer? Tumor-associated macrophages (TAMs) are immune cells that are the most abundant immune population in ovarian cancer. In this cancer they mostly exist in an immunosuppressive M2 state that promotes tumor growth, invasion, blood vessel formation, immune evasion and spread. Because they sit at the centre of these problems, they are a key target for new treatments. ### How do TAMs make ovarian cancer resistant to chemotherapy? M2-polarized TAMs are linked to drug resistance. In one study, co-culturing ovarian cancer cells with macrophages reduced carboplatin sensitivity in a dose-dependent way, alongside a shift to an M2-like phenotype. TAMs can also release exosomes carrying miR-223, which confers chemoresistance through the PTEN–PI3K/AKT pathway in laboratory and animal experiments. ### What is mirvetuximab soravtansine and who can receive it? Mirvetuximab soravtansine (MIRV) is an antibody–drug conjugate targeting folate receptor alpha (FRα), which is overexpressed on ovarian tumor cells. It is approved for FRα-positive, platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancers after one to three prior treatment regimens. In a phase III trial it caused fewer severe side effects and fewer dose reductions than standard chemotherapy. ### What does it mean if a trial reports an objective response rate? Objective response rate (ORR) is the proportion of patients whose tumors shrank or disappeared. In the phase II SORAYA trial, MIRV monotherapy produced a high ORR with durable responses in patients with FRα-high, platinum-resistant disease, regardless of prior therapies. It is a measure of tumor shrinkage, not of how long patients live. ### Are TAM-targeted treatments available now, or only in trials? Most TAM-targeted therapies are still in early-phase trials without definitive clinical validation. Some approaches, such as targeting periostin (POSTN), have not yet reached clinical testing at all. Mirvetuximab soravtansine, which targets FRα on tumor cells rather than TAMs, is approved for a specific platinum-resistant group. ### What risks or side effects are linked to these new approaches? On-target toxicity is a real concern, because depleting or reprogramming macrophages may affect similar cells elsewhere in the body that perform essential immune functions. In one mouse study, FRβ CAR-T treatment caused transient weight loss. CD47-blocking drugs can harm blood cells, so agents such as evorpacept and ligufalimab were designed to avoid that. ### Why do researchers say the M1/M2 macrophage classification is too simple? Single-cell analyses show macrophages exist on a functional continuum, not two neat categories. TAMs expressing CD163 or CD206, usually considered M2 markers, can show M1-like, T cell–activating properties in ovarian cancer ascites. Scientists also lack reliable markers that uniquely identify pro-tumoral TAM subsets in humans, which makes precise targeting difficult. ### I have platinum-resistant ovarian cancer — when should I seek a second opinion on my treatment options? A second opinion is worth considering when platinum-based chemotherapy stops working, since resistance is a central challenge and much of the treatment landscape is still evolving. Most therapies targeting tumor-associated macrophages remain in early-phase trials without definitive validation, and response varies with each tumor's immune environment. The approval of mirvetuximab soravtansine for FRα-positive, platinum-resistant disease shows that biomarker testing can open targeted options that may be less toxic than standard chemotherapy. An independent review can help clarify whether such options or a clinical trial fit your situation. Diagnostic Detectives Network provides independent expert second opinions. ## Source Information **Original article title:** Advance in therapies targeting tumor-associated macrophages in ovarian cancer. **Original authors:** Man Li, Yue Ma, Tinggeng Dai, Yongxin Wang, and Ying Yue (Department of Gynecological Oncology, The First Hospital of Jilin University, Changchun, China; reviewed by Lilong Zhang, Renmin Hospital of Wuhan University, and Yunfei Liu, Central South University, China) **Journal:** Frontiers in Immunology, Volume 16, Article 1677839 **Publication details:** Received 01 August 2025; Accepted 01 September 2025; Published 11 September 2025 **DOI:** 10.3389/fimmu.2025.1677839 **Copyright:** © 2025 Li, Ma, Dai, Wang and Yue. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). **Funding:** The authors declared that no competing financial interests or commercial relationships influenced the research. No generative AI was used in the creation of the original manuscript. *Note: This patient-friendly article is based on peer-reviewed research. Clinical trial identifiers (NCT numbers) are included to help interested readers locate ongoing studies. Always discuss treatment options with a qualified oncologist.* --- Publisher: Diagnostic Detectives Network (https://diagnosticdetectives.com) — independent multi-expert medical second opinions, worldwide, private-pay. Author byline: Anton Titov, MD, PhD. Contact: https://diagnosticdetectives.com/pages/contact Canonical page: https://diagnosticdetectives.com/products/turning-the-bodys-immune-cells-back-against-ovarian-cancer-new-ways-to-target-tumor-associated-macrophages