The dual role of CXCL9/SPP1 polarized tumor-associated macrophages in modulating anti-tumor immunity in hepatocellular carcinoma

The dual role of CXCL9/SPP1 polarized tumor-associated macrophages in modulating anti-tumor immunity in hepatocellular carcinoma

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IntroductionThe main challenge for cancer therapy lies in immuno-suppressive tumor micro-environment.Reprogramming tumor-associated macrophages (TAMs) into an anti-tumor phenotype is a promising strategy.MethodsA comprehensive analysis by combing multi-regional single-cell, bulk and spatial transcriptome profiling with radiomics characterization was conducted to dissect the heterogeneity of TAMs and resolve the landscape of the CXCL9:SPP1 (CS) macrophage polarity in HCC.ResultsTAMs were particularly increased in HCC.SPP1+ TAMs airpods in jacksonville and CXCL9+ TAMs were identified as the dominant subtypes with different evolutionary trajectories.

SPP1+ TAMs, located in the tumor core, co-localized with cancer-associated fibroblasts to promote tumor growth and further contributed to worse prognosis.In contrast, CXCL9+ TAMs, located in the peritumoral region, synergized with CD8+ T cells to create an immunostimulatory micro-environment.For the first time, we explored the applicability of CS polarity in HCC tumors and revealed several key transcription factors involved in shaping this polarity.Moreover, CS polarity could serve as a potential indicator of prognostic and micro-environmental status for HCC patients.Based on medical imaging data, skull bride and groom we developed a radiomics tool, RCSP (Radiogenomics-based CXCL9/SPP1 Polarity), to assist in non-invasively predicting the CS polarity in HCC patients.

ConclusionOur research sheds light on the regulatory roles of SPP1+ TAMs and CXCL9+ TAMs in the micro-environment and provides new therapeutic targets or insights for the reprogramming of targeted macrophages in HCC.