Low-dose bevacizumab plus atezolizumab enhances transarterial chemoembolization in HCC via correcting vascular-immune niche dysfunction.

BACKGROUND & AIMS: Transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) commonly results in residual disease; however, the angiogenic features of residual tumors remain poorly defined. This study aimed to characterize vascular niche remodeling after TACE and provide a translational rationale for optimizing combination therapy.

METHODS

We performed single-nucleus RNA sequencing on six treatment-naive and six post-TACE HCC tumor samples. The findings were subsequently validated across five independent cohorts using multiplex immunohistochemistry, plasma biomarker assays, public transcriptomic datasets, and retrospective clinical analyses. Multiple in vivo HCC models were further used to investigate the PDGFC-PDGFR axis and evaluate low-dose anti-VEGF-A plus anti-PD-L1 therapy.

RESULTS

Residual tumor vessels following TACE exhibited heightened angiogenic activity while remaining structurally immature, with accompanying immunosuppressive features. Integrated analyses revealed that TACE markedly reprogrammed tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) toward pro-angiogenic and immunosuppressive states. Notably, PDGFC+ TAMs acted on pericytes and CAFs to induce pericyte-to-CAF transition and activate stromal remodeling programs, thereby reinforcing a positive feedback loop linking aberrant angiogenesis and immunosuppression. More importantly, in preclinical HCC models, low-dose anti-VEGF-A plus anti-PD-L1 alleviated hypoxia, reduced PDGFC+ TAM accumulation, enhanced CD8+ T-cell immunity, and improved tumor control. Retrospective clinical analysis further supported the potential of low-dose bevacizumab plus atezolizumab to improve clinical outcomes while preserving hepatic function after TACE.

CONCLUSIONS

This study demonstrates that TACE induces PDGFC+ TAM-mediated dysfunction of the vascular-immune microenvironment. Low-dose bevacizumab plus atezolizumab may counteract this pathological microenvironment by promoting vascular normalization and enhancing antitumor immunity, thereby representing a promising therapeutic strategy.

IMPACT AND IMPLICATIONS: Transarterial chemoembolization (TACE) commonly leaves residual tumors in hepatocellular carcinoma (HCC); however, tumor angiogenic features in this context remain poorly defined. By integrating single-nucleus transcriptomics with multi-cohort validation, this study shows that residual tumors exhibit a hypoxic, angiogenic, and structurally immature vascular niche accompanied by immunosuppression. PDGFC+ tumor-associated macrophages emerged as a central component of this niche and may promote pericyte-to-fibroblast transition, cancer-associated fibroblast activation, and pathological angiogenesis. In preclinical HCC models, low-dose anti-VEGF-A plus anti-PD-L1 therapy alleviated hypoxia, reduced PDGFC+ macrophage accumulation, increased pericyte coverage, enhanced CD8+ T-cell immunity, and improved tumor control. Retrospective clinical analysis further suggested that low-dose bevacizumab plus atezolizumab may improve clinical outcomes while preserving hepatic function after TACE. These findings provide a translational rationale for further evaluating dose-optimized anti-angiogenic therapy plus immune checkpoint blockade in patients with HCC undergoing TACE.