Angiopoietin-like protein 4 deficiency promotes tumor immune infiltration and CD8+ T cell cytotoxic activity to inhibit tumor progression.

The tumor microenvironment (TME) exhibits immunosuppressive characteristics, hindering CD8+ T cell-mediated anti-tumor effects and restricting the efficacy of immune checkpoint inhibitors in some cancers. ANGPTL4, a secreted glycoprotein, is implicated in the regulation of lipid metabolism, angiogenesis, and inflammation, but its role in tumorigenesis, metastasis, and the modulation of the immune microenvironment requires further investigation. We compared the differences in tumor proliferation kinetics between in vitro and in vivo models of ANGPTL4 gene knockout, to determine the role of the TME in the cancer-promoting mechanism mediated by ANGPTL4. The absence of ANGPTL4 in tumor cells or the host can inhibit tumor proliferation and metastasis. Furthermore, ANGPTL4 absence was associated with extracellular matrix remodeling and the immune responses. We identified a correlation between the absence of ANGPTL4 and low expression of Ki-67 and vimentin. ANGPTL4 exhibited spatially variable expression in tumor tissues. Finally, we confirmed ANGPTL4 deficiency slowed tumor growth and markedly increased intratumoral CD8+ T cell infiltration. Transcriptomic analyses further revealed upregulation of adaptive immune pathways, including IFN-γ production, and T cell priming in ANGPTL4-deficient tumors. Together, these results show that the loss of ANGPTL4 reprograms the TME toward a more immune-active state, enhancing CD8+ T cell-mediated anti-tumor responses.