p53 is known to exert cell-intrinsic tumour suppression through cell cycle arrest, apoptosis and cellular senescence. Lujambio et al. now report that p53 promotes non-cell-autonomous tumour suppression, by triggering an anti-tumorigenic microenvironment that regulates macrophage function (Cell 11, 449–460; 2013).

Liver tumour initiation is often linked to fibrosis caused by hepatic stellate cell (HSC) proliferation. p53 is known to limit liver fibrosis by promoting HSC senescence, production of extracellular matrix and immune response regulators that comprise the senescence-associated secretory phenotype (SASP), and senescent cell clearance by immune cells. The authors demonstrated that conditional p53 deletion in HSCs promotes liver cirrhosis and mortality in mice and also results in increased non-cell-autonomous tumour formation by epithelial cells. Gene expression analyses determined that p53 regulates the SASP, immune signalling and protein secretion components in senescent HSCs, which displayed preferential secretion of macrophage-regulating cytokines. Moreover, p53-proficient senescent HSCs promoted macrophage polarization towards the anti-tumorigenic M1 subclass, which was able to eliminate senescent HSCs in co-culture experiments and was enriched in p53-positive damaged mouse livers. In contrast, p53-deficient proliferating HSCs enhanced the prominence of the pro-tumorigenic M2 macrophages, which increased premalignant cell proliferation in culture.

These findings reveal that p53 mediates a tumour-cell-extrinsic anti-tumorigenic response by controlling the SASP and macrophage polarization to limit liver damage and subsequent tumour formation.