Preclinical studies indicate that cavity-resident macrophages in the peritoneal and pleural spaces contribute to immunosuppression and cancer progression. While these macrophages typically accumulate on organ surfaces rather than deeply infiltrating into tissues, their behavior and function in tumors remains unclear. Using dual recombinase-mediated genetic lineage tracing in a B16F10 melanoma lung metastasis model, this study demonstrated that pleural cavity macrophages (GATA6⁺CD45⁺) infiltrate lung tumors and contribute to a significant proportion of tumor-associated macrophage. Genetic ablation or sequestration of these macrophages markedly suppressed tumor growth, underscoring their pro-tumorigenic function.

To investigate their recruitment, Gata6-iCreER mice were crossed with Cd45-Dre and R26-tdT mice, enabling specific lineage tracing of cavity macrophages. Flow cytometry and immunofluorescence confirmed their infiltration into lung tumors, where they constituted for ~50% of tumor-associated macrophages. Similar observations were made in Hepa1-6 and LLC metastasis models, suggesting a broad role across tumor types.

To assess functional relevance, a Gata6-RSR-tdT-DTR mouse model was developed for diphtheria toxin (DT)-mediated macrophage depletion. DT treatment significantly reduced tumor burden and extended survival, confirming their pro-tumor effects. Gata6 knockout in cavity macrophages significantly suppressed metastasis. However, cell depletion after tumor establishment showed limited efficacy, indicating their primary role in early tumor growth.

Mechanistically, macrophage depletion increased cytotoxic CD8⁺ T cells in tumors and pleural cavities, suggesting that cavity macrophages suppress anti-tumor immunity. These findings establish cavity macrophages as key drivers of tumor progression and propose their targeting as a potential therapeutic strategy. Further research is needed to elucidate the molecular mechanisms driving their migration and immunosuppressive functions.

DOI:10.1093/procel/pwaf078