As tumour protein 53 (p53) isoforms have tumour promoting migration and inflammatory properties this study investigated if p53 isoforms contributed to glioblastoma and prostate cancer progression. Elevated levels of Δ133TP53β mRNA characterised glioblastomas and prostate cancers with increased CD163 and CSF1R positive macrophages, wild-type p53, and increased PDL1 positive cells. Consistent with this, RNAseq of tumors showed enrichment for pathways associated with immunosuppression and cell migration. We further show a role for hypoxia and wild-type p53 in upregulating Δ133TP53β. In glioblastoma elevated Δ133TP53β was associated with reduced overall patient survival, and in prostate cancer AUC analysis showed that a combination of three markers (Δ133TP53β, T-cell and macrophage content) predicted aggressive disease with 93% accuracy. Whether tumours with elevated Δ133TP53β could be better imaged before surgery for improved surgical resection is currently being determined as part of a new clinical trial involving glioblastoma patients. This trial aims to identify the associated macrophage content across the whole tumour using MRI. In summary, our findings suggest elevated Δ133TP53β is an alternative pathway to p53 mutation that aids tumour progression by promoting an immunosuppressive environment.