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. 2022 Oct 10;22(2):127–144. doi: 10.1038/s41573-022-00571-8

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Fig. 5 — In p53-wild-type (wtp53) tumours, the tumour immune microenvironment has a predominantly anti-tumoural effect. This can be attributed to several mechanisms. For example, wtp53 can upregulate the expression of UL16-binding protein 1 (ULBP1) and ULBP2 and microRNA miR-34a. ULBP1 and ULBP2 are activating ligands for natural killer (NK) cells, which enhances their cytotoxic activity. miR-34 blocks the translation of PDL1 mRNA and drives its degradation; consequently, PDL1 protein levels are downregulated in cancer cells that retain wtp53, sensitizing these tumour cells to CD8⁺ T cell-mediated killing. Moreover, wtp53 can promote the secretion of anti-tumoural cytokines such as tumour necrosis factor (TNF), which further enhances the protective effects of the tumour immune microenvironment. In TP53-mutated cells, ULBP1 and ULBP2 are downregulated and PDL1 is upregulated, causing resistance to killing by NK and CD8⁺ T cells, respectively. Furthermore, loss of p53 function can drive secretion of WNT ligands, which bind to their cognate receptors on macrophages, causing them to secrete IL-1β, which attracts pro-tumoural cells such as neutrophils. Mutp53 proteins promote the secretion of exosomes that can deliver microRNAs such as miR-1246, which convert anti-tumoural M1 macrophages to pro-tumoural M2 macrophages. Such pro-tumoural macrophages secrete IL-1β, which attracts pro-tumoural regulatory T (T_reg) cells that dampen the anti-tumoural response and protect the tumour from immune elimination. MHC-I, major histocompatibility complex class I; RE, response element; TCR, T cell receptor.