TP53 mutants (mutp53) are involved in the pathogenesis of most human cancers. Specific
mutp53 proteins gain oncogenic functions (GOFs) distinct from the tumor suppressor activity
of the wild-type protein. Tumor-associated macrophages (TAMs), a hallmark of solid tumors,
are typically correlated with poor prognosis. Here, we report a non-cell-autonomous
mechanism, whereby human mutp53 cancer cells reprogram macrophages to a tumor supportive and anti-inflammatory state. The colon cancer cells harboring GOF
mutp53 selectively shed miR-1246-enriched exosomes. Uptake of these exosomes by
neighboring macrophages triggers their miR-1246-dependent reprogramming into a cancerpromoting state. Mutp53-reprogammed TAMs favor anti-inflammatory immunosuppression
with increased activity of TGF-β. These findings, associated with poor survival in colon cancer
patients, strongly support a microenvironmental GOF role for mutp53 in actively engaging the
immune system to promote cancer progression and metastasis
