Tumor-Associated Macrophages Emerge as Central Drivers of Gastric Cancer Peritoneal Metastasis and Immunotherapy Resistance
核心洞察
Tumor-associated macrophages (TAMs) are the dominant immune population in the peritoneal cavity and orchestrate nearly every step of gastric cancer (搜索) peritoneal metastasis (搜索), from tumor cell detachment to immune evasion.
Peritoneal metastasis (搜索) carries a devastating prognosis, with median survival shortened to only 3–6 months after recurrence, and up to 50% of patients experience peritoneal recurrence following curative-intent surgery.
Emerging single-cell studies reveal TAMs shift from a cathepsin (CTS)-high to a complement C1q (搜索)-high state that upregulates PD-L1 (搜索) and NECTIN2, driving immune escape and identifying new therapeutic targets.
Tumor-associated macrophages (TAMs) are the most abundant immune cells in the peritoneal cavity and act as central orchestrators of gastric cancer (搜索) peritoneal metastasis (搜索)—the most devastating form of disease progression, marked by profound immune suppression and treatment resistance. A comprehensive review published in Frontiers in Immunology synthesizes the latest evidence on how gastric cancer cells exploit macrophage plasticity through metabolic signals, exosomal oncomiRs, and paracrine factors to drive a pro-metastatic phenotype, while also outlining emerging macrophage-directed therapeutic strategies.
Peritoneal metastasis (搜索) carries an exceptionally poor prognosis. At initial diagnosis, roughly 14% of patients already show signs of peritoneal metastasis, and among those undergoing curative-intent surgery for advanced disease, up to 50% will develop peritoneal recurrence. Once recurrence occurs, median survival is shortened to only 3 to 6 months. Treatment outcomes remain poor largely because the peritoneal cavity forms an immunosuppressive environment: systemic chemotherapy is limited by the peritoneal barrier, which keeps drug concentrations far lower than in the bloodstream, while molecularly targeted drugs and immunotherapy—effective in many solid tumors—have little effect on peritoneal metastatic foci.
Dual Origins and Functional Plasticity of Peritoneal Macrophages
Peritoneal macrophages arise from two major lineages. Tissue-resident macrophages originate from embryonic precursors in the yolk sac or fetal liver, express the transcription factor GATA6 and surface markers such as TIM4 and ICAM2, and concentrate in the milky spots of the greater omentum—the primary attachment site for early peritoneal dissemination. The second lineage involves circulating monocytes recruited into the peritoneal cavity through CCR2 (搜索)-mediated chemotaxis, which then differentiate into macrophages expressing low GATA6 but high CCR2 and CD226. As tumors progress, monocyte-derived macrophages increase in number, particularly in patients with late malignant ascites.
The review emphasizes that the classical M1/M2 dichotomy is insufficient to capture in vivo macrophage biology. Single-cell RNA sequencing of malignant ascites from gastric cancer (搜索) patients has identified multiple macrophage subtypes—including CTS-high and C1q (搜索)-high TAMs—that can simultaneously express inflammatory and pro-tumor genes. "Macrophages are not locked into terminal M1 or M2 states but instead exist on a continuous, context-dependent polarization gradient," the authors note, underscoring the plasticity of TAMs in the peritoneal metastatic microenvironment.
Mechanisms of Pro-Tumor Reprogramming
Gastric cancer (搜索) cells actively reprogram macrophages through several interrelated mechanisms. At the metabolic level, tumor-derived lactate guides macrophages toward an M2 state via the mTOR/HIF-1α pathway, stabilizing HIF-1α to bind hypoxia-response elements in promoters of M2-associated genes such as Arg1, CD206, and IL-10. Lactate also serves as a substrate for histone lactylation, an epigenetic modification that promotes transcription of pro-tumor genes and facilitates formation of the pre-metastatic niche. Fatty acids released by cancer cells upregulate CD36 on TAMs, further driving M2 polarization.
Exosome-mediated communication provides another layer. Under hypoxia, cancer cells package microRNAs such as miR-21-3p into exosomes in a process regulated by HIF-1α and HIF-2α, promoting M2 polarization upon macrophage uptake. A recent study showed that elevated METTL3 in gastric cancer (搜索) cells enhances m6A methylation and exosome biogenesis; the released exosomes carry miR-17–92 clusters that target SRCIN1 in macrophages, activating SRC signaling and inducing immunosuppressive cytokine release. Paracrine factors—including CSF1 and CCL2 secreted by cancer cells—recruit monocytes and guide their differentiation toward M2 macrophages.
Orchestrating the Metastatic Cascade
TAMs participate in nearly every step of peritoneal metastasis (搜索). They promote tumor cell detachment by releasing TGF-β and TNF-α, which activate EMT transcription factors Snail, Slug, and ZEB1, and by secreting MMP2 and MMP9 to degrade the basement membrane. M2 macrophages secrete CCL18, which binds PITPNM3 receptors on cancer cells to enhance migration, while macrophage-derived fibronectin (FN1) upregulates SDC4 to inhibit Hippo signaling and accelerate peritoneal spread.
Once tumor cells enter the peritoneal cavity, TAMs help them resist anoikis through IL-6 and TNF-α-mediated activation of NF-κB and STAT3, upregulating anti-apoptotic proteins such as Bcl-2 and Survivin. TAM-secreted Gas6 binds Axl receptors to activate PI3K/Akt, while TAM-derived GDNF regulates autophagy via GFRA1 signaling to help cancer cells tolerate metabolic stress. Macrophages also disrupt the mesothelial barrier through MMP2/MMP9 and promote adhesion by upregulating integrins (α5β1 and αvβ3) and releasing fibronectin and osteopontin.
For metastatic nodule growth, TAMs drive angiogenesis and lymphangiogenesis by releasing VEGF, IL-1β, TGF-β1, TNF-α, bFGF, and IL-10. M2-like TAMs are the main source of VEGF-C and VEGF-D, which bind VEGFR-3 on lymphatic endothelial cells to stimulate lymphatic vessel growth—a process the review notes is especially critical for peritoneal spread compared with other organ metastases.
Immune Evasion and Chemoresistance
TAMs establish a self-reinforcing immunosuppressive microenvironment. M2 macrophages release IL-10 and TGF-β to block CD8+ T cell activation, recruit Tregs via CCL22/CCR4, drive CD8+ T cell exhaustion through PD-L1 (搜索)/PD-1 and Galectin-9/TIM-3, and promote MDSC recruitment via CXCL1/2/5, IL-6, PGE2, and S100A8/A9. TIM4+ macrophages phagocytose apoptotic CD8+ T cells, while TIM3+ TAMs further suppress T cell-mediated responses.
Macrophages also directly promote chemoresistance. M2 TAMs release IL-6 and TNF-α to activate NF-κB and STAT3 in cancer cells, upregulating Bcl-xL and Survivin, and act as a "drug barrier" by clearing chemotherapy agents through phagocytosis. Exosomal miR-21 from M2 macrophages targets PTEN, activates PI3K/Akt, and confers cisplatin resistance.
Key Signaling Networks and the C1q Lineage Switch
The CCL2/CCR2 (搜索) axis drives macrophage recruitment, while the CSF-1/CSF-1R (搜索) axis provides survival and proliferation signals through PI3K/Akt and MAPK/ERK pathways. STAT3 and STAT6 serve as principal transcription drivers of M2 polarization, and PI3Kγ mediates polarization through the Akt/mTOR axis. In the immunosuppressive peritoneal environment, NF-κB forms p50/p50 homodimers that activate M2-associated genes such as IL-10 and CD206.
A pivotal single-cell study by Li and colleagues, analyzing ascites from 63 gastric cancer (搜索) patients with peritoneal metastasis (搜索), revealed that TAMs transition from a CTS-high to a C1q (搜索)-high state. CTS-high TAMs secrete CTSS and CTSL to recruit disseminated tumor cells, then differentiate into C1q-high TAMs that activate the classical complement pathway and significantly upregulate PD-L1 (搜索) and NECTIN2 on tumor cells, accelerating proliferation and immune escape. This identifies C1q-high TAMs and downstream complement products such as C3a and C5a as potential therapeutic targets, with anti-C1q monoclonal antibodies and C5aR antagonists showing promise in preclinical studies—though the authors caution these findings require independent validation.
Therapeutic Strategies Targeting Macrophages
Macrophage-directed strategies fall into two categories. The first directly targets macrophages by blocking recruitment (CSF-1/CSF-1R (搜索) or CCL2/CCR2 (搜索) inhibition) or reprogramming polarization. PI3Kγ inhibitors such as IPI-549 can convert M2 macrophages toward an anti-tumor M1 state, while TLR7/8 agonists and nanoparticle-encapsulated agents (such as miR-let-7a targeting IRS2) offer precision reprogramming with reduced systemic toxicity.
The second category leverages cellular and physical approaches. CAR-macrophage (CAR-M) therapy, unlike CAR-T cells, can directly kill tumor cells while also reshaping the microenvironment and presenting antigens. In mouse models of HER2 (搜索)-overexpressing peritoneal metastasis (搜索), macrophages engineered to express an FcεR1γ chimeric antigen receptor targeting HER2 (HF CAR-PMs) significantly promoted tumor regression and prolonged overall survival. A clinical trial of HER2-targeted CAR-M for patients with HER2-positive advanced gastric cancer (搜索) with peritoneal metastasis (NCT06224738) is currently underway. Hyperthermic intraperitoneal chemotherapy (HIPEC) remains an important option, with part of its effect potentially mediated by macrophages—heating alone can shift macrophage phenotype and enhance tumor-cell engulfment.
The authors highlight several unresolved challenges, including incomplete understanding of macrophage heterogeneity across anatomical sites, the role of senescent TAMs, limitations of current animal models, and the risk of systemic side effects from macrophage-targeted therapy. They emphasize that combining macrophage-directed approaches with chemotherapy, immunotherapy, or HIPEC represents a rational strategy to overcome immune checkpoint inhibitor resistance and improve outcomes in this devastating disease.