Tumour-associated macrophages (TAMs) are highly enriched in solid tumours and critically shape microenvironmental conditions and tumour progression. Here we uncover that invasive, metastatic amoeboid cancer cells actively recruit monocytes and polarise them into a distinct tumour-promoting macrophage state, which we define as Amoeboid-Associated Macrophages (AAMs).

To characterise this macrophage state, we performed integrative transcriptomic, proteomic/phosphoproteomic, and lipidomic analyses combined with spatial transcriptomics, mass spectrometry imaging, and digital pathology.

These analyses reveal that AAMs engage a coordinated programme encompassing wound-healing, chemotaxis, lipid metabolism, inflammatory signalling, and immunosuppression. AAMs exhibit a CD206⁺MARCO⁺PD-L1⁺ phenotype driven by elevated STAT3 activity and associated with enhanced cytoskeletal dynamics. Molecularly, AAMs resemble a specialised lipid-associated macrophage subset and are spatially enriched at the tumour–stroma interface and metastatic borders. Integrating mass spectrometry imaging with digital pathology identifies a convergent enrichment of specific fatty acids, amoeboid cancer cells, AAMs, and adipocytes within these peripheral tumour regions. Functionally, AAMs adopt a pro-survival and pro-migratory programme that directly supports amoeboid cancer cell invasion. Furthermore, AAMs generate a distinctive repertoire of inflammatory lipid mediators and are associated with resistance to immunotherapy.

Pharmacological STAT3 inhibition effectively reprogrammes AAMs, highlighting a therapeutic avenue to disrupt their tumour‑supportive functions. Importantly, markers of this macrophage state are detectable across multiple solid tumour types, and their abundance correlates with poor patient prognosis, underscoring the broad clinical relevance of this newly defined tumour‑ecosystem component.

Work supported by the Institute of Cancer Research, Cancer Research UK, Breast Cancer Now, Barts Charity, Worldwide Cancer Research, and UKRI. We would like to acknowledge several other co-authors working under a consortium of collaborators at the The Institute of Cancer Research, National Physics Laboratory, Barts Cancer Institute, Genome Centre QMUL and the William Harvey Research Institute.