Profiling the tumor microenvironment of a hepatocellular carcinoma patient with primary resistance to immunotherapy plus anti-angiogenic therapy but exceptional response to chemotherapy plus bevacizumab

Abstract

Hepatocellular carcinoma (HCC) with extrahepatic metastasis (EHM) carries a poor prognosis, and treatment options after failure of anti-angiogenic targeted agents combined with immune checkpoint inhibitor (ICI) remain limited. An adult patient with advanced HCC exhibited primary resistance to three sequential immunotherapy-based regimens: first-line lenvatinib plus camrelizumab (progressive lung metastases), second-line atezolizumab plus bevacizumab (rapid tumor marker surge), and third-line atezolizumab plus regorafenib (new liver and adrenal metastases within 3 months, suspicious for rapid disease progression following immunotherapy). Fortunately, fourth-line mFOLFOX6 chemotherapy (oxaliplatin, leucovorin, and fluorouracil) plus bevacizumab induced a partial response (PR) with significant tumor shrinkage and substantial declines in AFP and PIVKA-II. The case had shown a total progression-free survival (PFS) for more than 21 months until the latest follow-up in June 2026. Then, we performed 24-plex spatial tissue profiling of the primary tumor. The tumor microenvironment revealed three core features: immune-desert (lymphocytes < 5%, no tertiary lymphoid structures, exhausted PD-1 + CD8+ T cells), hyper-vascularization with disorganized endothelium and severe pericyte deficiency (αSMA coverage 2.9%), and high perivascular tumor proliferation. This unique “immune-desert, vessel-rich, rapidly proliferating” signature potentially accounts for the striking oxaliplatin-based chemotherapy sensitivity despite primary ICI-anti-angiogenic therapy resistance. This case suggests that in selected HCC patients with multiline ICI-anti-angiogenic therapy resistance, prompt transition to chemotherapy plus bevacizumab may yield profound responses.