our analysis showed that camls indeed co - localised with at2 cells ( fig. 4g, h ). we confirmed this finding using non - negative matrix factorisation ( nmf ) on the absolute cell - type abundances estimated by cell2location that defined factors of co - occurring cell states ( fig. 4i ). to determine the specific mɸ population from which camls likely originate, we employed paga to elucidate the differentiation path of the myeloid cell population in our tumour dataset ( supplementary fig. 5d ). the analysis revealed continuity of the differentiation transitions between diverse populations of myeloid cells. within the paga trajectory, alveol ar mɸ ( amɸ ) and aimɸ showed high paga connectivity indicating their high transcriptional similarity. both aimɸ and amɸ showed the strongest connectivity on the paga trajectory with stab1 + mɸ which, in turn, were linked with camls. in line with trajectory analysis, camls co - expressed many of the genes specific to stab1 + mɸ ( supplementary fig. 2a ), supporting the hypothesis that camls are likely derived from stab1 + mɸ following their close interaction with tumour cells. finally, dea analysis between camls from lusc versus luad patients, showed upregulation of krt17, krt5 and krt6a in lusc samples ( supplementary data 17 ). these krt genes were previously identified as markers of lusc in multiple studies, which supports hypothesis that camls arise from the interaction between mɸ and tumour cell. mɸ, traditionally categorised into distinc t m1 ( classically activated ) and m2 ( alternatively activated ) phenotypes, are now understood to exist along a dynamic spectrum of functional states. this concept of mɸ plasticity underscores their ability to seamlessly transition between pro - inflammatory and anti-inflammatory roles in response to intricate cues from their microenvironment ( supplementary fig. 5d ). to better understand the transcriptional changes that different mɸ populations undergo in the tme, we performed dea. in tumours, both amɸ and aimɸ upregulated genes involved in cholesterol and lipid transport and metabolism ( such as abca1, apoc1, apoe, fabp3 and fabp5 ) compared to the background tissue ( fig. 5a, b and supplementary data 18 and 19 ). cholesterol plays a vital role in tumour growth due to the high demand of newly synthesised cellular membranes during cancer cell proliferation. hypoxia - related genes were upregulated in at2 cells in tumour compared to the background ( fig. 4d ), which can promote cholesterol auxotrophy in tumour cells by suppressing cholesterol synthesis, thereby forcing them to rely on exogenous cholesterol uptake. in our dataset, we detected higher expression of the cholesterol exporter abca1 and no expression of low - density lipoprotein receptor ( ldlr ) in amɸ and aimɸ, the latter gene being responsible for the uptake of cholesterol - carrying lipoprotein particles into cells, suggesting preferential export of cholesterol from tams to the tme ( fig. 5a ). interestingly, we also noted a high expression of trem2 in both amɸ and aimɸ ( fig. 5a ), which plays a prominent role in efflux of cholesterol in microglia. to validate the increased levels of cholesterol in the tme, we stained matched tumour and background tissue sections with bodipy™ 493 / 503, a stain targeting cholesterol and other neutral lipids. we found a significant increase in the bodipy signal in the tumour sections, compared to background tissue ( fig. 5c, d ), confirming an increased availability of neutral lipids in the tumour, possibly as a result of an increased export by tams. stab1 + mɸ were identified in the tumour resections ( fig. 5e – h, supplementary fig. 2 and supplementary notes ), so we used dea to identify a set of genes that were specific for stab1 + mɸ compared to tumour aimɸ or amɸ. we identified 20 genes, from here on referred to as “ stab1 signature genes ” ( fig. 5i ). interestingly, stab1 + mɸ uniquely expressed slc40a1, which encodes for the ferroportin, the only known protein that exports ferrous iron from the cytoplasm across the plasma membrane and is key for the iron - releasing activity of macrophages ( fig. 5i, j and supplementary data 20 and 21 ). ferroportin - mediated release of free iron by m2 mɸ was reported to promote the proliferation of renal carcinoma cells in vitro, possibly by supporting the high iron requirement due to increased dna synthesis. furthermore, compared to amɸ, stab1 + mɸ expressed lower levels of ferritin heavy chain 1 ( fth1 ) and ferritin light chain ( ftl ) encoding for the iron storer ferritin ( fig. 5j and supplementary data 20 ). consistent with the hypothesis of their sustained export of free iron to the extracellular milieu, stab1 + mɸ downregulated genes involved in iron sequestration ( fig. 5k ). taken together, our analysis suggests that macrophages undergo “ reprogramming ” within the tme and adopt a transcriptional signature that facilitates cholesterol efflux and iron export, thus supporting tumour progression. embryonic development shares many characteristics with tumour tissue, including rapid cell division, cellular flexibility, and a highly vascular microenvironment. it has been recently reported that during tumorigenesis, mɸ can undergo oncofoetal reprogramming and acquire a foetal - like transcriptional identity that supports tumour growth and metastasis. considering that some of the stab1 signature genes are typically expressed by foetal mɸ ( such as stab1, folr2, slc40a1, mertk, gpr34 and f13a1 ), we wanted to explore if further transcriptional commonalities exist between tumour - originating stab1 + mɸ and mɸ isolated from human foetal lung. to this end, we combined tumour - and background - originating myeloid cells from our dataset ( n = 347, 364 cells ) with myeloid and progenitor cells from a publicly available foetal lung scrna - seq dataset ( n = 6, 947 cells ) using harmony. next, we performed leiden clustering on the neighbourhood graph and examined how cell types are distributed within the clusters ( supplementary fig. 6a, b ). to examine similarity in their gene expression profile, we applied hierarchical clustering and built a dendrogram by estimating the correlation distance between cell types on the harmonised pc embedding space, under the complete linkage criterion of hierarchical clustering ( fig. 6a ). we observed that tumour cdc2 exhibited the strongest correlation with background cdc2, whereas tumour mo - dc2 displayed the highest correlation with foetal dc2 and, in a broader context, with background mo - dc2. the population of pdc from tumour, background and foetal lung were closely correlated. similarly, tumour monocytes were correlated with foetal classical monocytes and background monocytes. in contrast, macrophage populations in tumour, and in particular stab1 + mɸ, were correlated with foetal macrophages. stab1 + mɸ clustered predominantly with foetal spp1 + mɸ ( fig. 6a ), which accounted for over 80 % of all foetal lung macrophages reported in ref.. consistent with this finding, spp1 + mɸ had a high expression of the “ stab1 signature genes ” compared to other haematopoietic populations ( fig. 6b, c ). our analysis substantiate s the idea that monocytes within the tumour environment, as they undergo differentiation into anti-inflammatory macrophages, acquire a transcriptional signature akin to that of foetal macrophages. this distinc tive transcriptional signature was not observed in the macrophages from surrounding normal tissue. to further examine the prevalence of stab1 + mɸ in other pathologies, including other cancers, we examined the expression of “ stab1 signature genes ” across a diverse group of myeloid cells using a published atlas of human monocytes and mɸ collected from 12 different healthy and pathologic tissues ( n = 140, 327 cells ), called momac - verse.