Tumor-associated macrophages (TAM) have peculiar membrane phenotype and functional properties. In an effort to unravel possible molecular determinants associated with the reprogramming of mononuclear phagocytes that infiltrate tumors, we have investigated the expression of immediate-early genes in TAM from murine sarcomas. c-fos is a prototypic immediate oncogene, with transregulatory function on gene transcription, expressed by myelomonocytic cells and induced by certain activation signals. TAM from three murine sarcomas expressed basal levels of c-fos transcripts considerably higher than those of peritoneal exudate macrophages (PEM). Activation of myelomonocytic cells by bacterial LPS is associated with an early transient increase in c-fos transcription. Unlike PEM, TAM did not show any increase in c-fos expression after exposure to LPS. A similar unresponsiveness to LPS stimulation was observed in macrophages isolated from peritoneal ascitic tumors. c-fos expression in macrophages can be induced via protein kinase C activation or via an increase in cAMP levels. Unlike PEM, TAM did not respond to the protein kinase C activator PMA and to cholera toxin. After culture for 18 to 20 h, c-fos expression in TAM declined, and concomitantly, TAM completely recovered responsiveness to LPS in terms of augmented oncogene mRNA levels. These results demonstrate that TAM from murine sarcomas have an altered expression of the c-fos proto-oncogene, with high basal levels and unresponsiveness to augmenting signals, reversible upon in vitro culture. The altered c-fos expression in TAM may reflect exposure to cytokines present in the tumor microenvironment and may underlie at least some of the peculiar properties of TAM.