PLAGL2 promotes HCC progression by recruiting tumour‐associated macrophages via CCL2/CCR2 signalling

Abstract Background and Purpose Tumour‐associated macrophages (TAMs) constitute the predominant cell population within the tumour microenvironment and play a crucial role in promoting the progression of primary hepatocellular carcinoma (HCC). Our previous study has identified PLAGL2 as a driver of HCC progression; however, the comprehensive regulation of PLAGL2 on the immunosuppressive microenvironment of HCC has not been fully elucidated. The objective of this study is to elucidate the molecular mechanism by which PLAGL2 regulates TAMs. Experimental Approach Mouse orthotopic liver cancer, subcutaneous tumour, and in vitro co‐culture models demonstrated PLAGL2's regulation of TAM recruitment/polarisation. Single‐cell sequencing and Flow cytometry assessed immune cell subpopulation changes. Key Results Our study found that the expression of PLAGL2 was positively correlated with the recruitment of TAMs, M2 polarisation and poor prognosis. PLAGL2 promoted macrophage migration and M2 polarisation in vitro and in vivo. Single‐cell analysis revealed that overexpression of PLAGL2 in HCC cells mainly recruited CCR2 + macrophages. Deletion of macrophages attenuated the promotion of HCC growth by PLAGL2. Mechanistically, PLAGL2 directly participated in the transcriptional regulation of CCL2, thereby initiating its transcription and expression. Moreover, pharmacological inhibition of CCR2 significantly inhibited PLAGL2‐induced HCC progression, TAM recruitment and M2 polarisation. Conclusions and Implications PLAGL2 participates in the chemotaxis of TAMs and the regulation of M2 polarisation through the CCL2–CCR2 axis, thereby promoting an immunosuppressive microenvironment in HCC. Additionally, this study demonstrated that PLAGL2 serves as a novel transcription factor for CCL2, suggesting that PLAGL2 is a potential drug target for the treatment of HCC.