Immunotherapy Breakthroughs and Single-Cell Atlas Studies Reshape Liver Cancer Care in China

Hepatocellular carcinoma, the dominant form of primary liver cancer, remains one of the most formidable public health challenges facing China. The country ranked fourth in cancer incidence and second in cancer mortality in recent national surveillance data, and in 2020 it accounted for nearly half of the world’s new liver cancer cases and deaths. The five-year survival rate sits at a sobering 12.1 percent. A comprehensive 2023 review published in Clinical Cancer Bulletin by researchers at Fudan University’s Zhongshan Hospital now synthesizes a remarkable year of progress across both clinical trials and laboratory science, documenting how Chinese investigators are attacking the disease from every angle, from perioperative drug regimens to spatially resolved molecular atlases of tumor tissue.

The clinical problem is defined by timing. Most Chinese patients are diagnosed at an advanced stage, when curative surgery is no longer an option, and even those who undergo resection frequently relapse as recurrence and metastasis erode treatment gains. Drug therapy has therefore become an indispensable pillar of hepatocellular carcinoma management, and the arrival of immune checkpoint inhibitors, antibodies that release the molecular brakes tumors place on T cells, has transformed the pharmacological landscape. The 2023 review highlights how these agents are now being pushed into new territory: before surgery, after surgery, and in combination with local therapies such as transarterial chemoembolization.

Neoadjuvant treatment, given before tumor resection to shrink tumors and downstage disease, emerged as one of the hottest clinical research areas of the year. At the 2023 annual meeting of the American Society of Clinical Oncology, Guo and colleagues presented a multicenter, phase III, randomized controlled trial of preoperative FOLFOX chemotherapy, a regimen of folinic acid, fluorouracil, and oxaliplatin, delivered by hepatic arterial infusion in 392 patients with resectable Barcelona Clinic Liver Cancer stage A or B tumors beyond the Milan criteria. The treated group achieved significantly better overall survival and recurrence-free survival than the control group, providing some of the strongest evidence yet that treating the tumor before the scalpel can confer a genuine survival advantage.

Immunotherapy is also entering the preoperative arena. Zhou and colleagues reported a phase II/III study of camrelizumab, an anti-PD-1 antibody, combined with the anti-angiogenic drug apatinib as perioperative treatment for resectable hepatocellular carcinoma at intermediate to high risk of recurrence. Among 119 patients with Chinese Liver Cancer stage Ib to IIIa disease, the neoadjuvant combination achieved a major pathological response, meaning extensive tumor destruction in the resected specimen, in 40 percent of patients overall and 46.2 percent of those who underwent resection, with favorable safety. A definitive phase III trial is now underway, and the field awaits large-scale confirmation that immunotherapy plus targeted therapy before surgery can become standard practice.

On the other side of the operation, adjuvant therapy scored what the review calls a major breakthrough. The IMbrave050 study, the first global phase III trial of postoperative adjuvant systemic therapy in hepatocellular carcinoma, enrolled 668 patients at high risk of recurrence and randomly assigned them to one year of atezolizumab plus bevacizumab or to active surveillance. The combination raised the one-year recurrence-free survival rate from 65 to 78 percent, a 13 percent absolute improvement corresponding to a 28 percent reduction in recurrence risk. Complementing this, a multicenter phase II trial of the anti-PD-1 antibody sintilimab as a single agent extended median recurrence-free survival to 27.7 months versus 15.5 months with monitoring alone, cutting recurrence risk by 47 percent. Adjuvant hepatic arterial infusion chemotherapy with FOLFOX likewise improved disease-free survival from 10.0 to 20.3 months in patients whose tumors showed microvascular invasion, a notorious predictor of relapse.

For advanced disease, combination strategies dominated. The LAUNCH trial demonstrated that lenvatinib plus transarterial chemoembolization extended median overall survival to 17.8 months compared with 11.5 months for lenvatinib alone as first-line therapy. In the second-line setting, pembrolizumab significantly prolonged outcomes versus placebo in Asian patients with previously treated advanced disease, and the RATIONALE-301 study showed tislelizumab was noninferior to sorafenib in overall survival as first-line treatment. The most striking result came from the international phase III CARES-310 trial, in which camrelizumab plus apatinib beat sorafenib on both progression-free survival, 5.6 versus 3.7 months, and overall survival, 22.1 versus 15.2 months, delivering survival benefits across subgroups and establishing a new benchmark for first-line therapy.

Loco-regional and systemic treatments are increasingly being woven together. The EMERALD-1 trial, the first multicenter phase III study of immunotherapy combined with an anti-angiogenic drug and transarterial chemoembolization, enrolled 616 patients with unresectable hepatocellular carcinoma from 18 countries and showed that durvalumab plus bevacizumab added to embolization significantly improved progression-free survival with tolerable toxicity. The real-world CHANCE001 study confirmed that adding PD-1 or PD-L1 inhibitors and targeted agents to embolization improved progression-free survival, overall survival, and response rates in Chinese patients. The DurHope study reported an objective response rate of 47.4 percent with FOLFOX hepatic arterial infusion chemotherapy plus durvalumab even in patients with severe portal vein tumor thrombosis, one of the disease’s most ominous complications, while the START-FIT approach of sequential embolization, stereotactic body radiotherapy, and PD-L1 blockade showed promising conversion results in locally advanced tumors.

Beneath these clinical advances, basic researchers deployed single-cell sequencing and spatial omics to dissect the tumor’s inner architecture. Sun and colleagues built the first spatiotemporal multi-omics atlas of hepatocellular carcinoma metastasis, revealing the molecular timing of metastatic initiation, the clonal patterns of spread, and the selection pressures that shape them. Spatial transcriptomics uncovered a tumor immune barrier, a defensive structure formed by SPP1-positive macrophages and cancer-associated fibroblasts that blocks immune cell infiltration and correlates with poor immunotherapy response. Using the ultra-high-resolution Stereo-seq platform, another team mapped the liver cancer landscape cell by cell and defined a tumor invasion front, a dynamic border ecosystem whose cellular interactions dictate invasion trajectory and patient prognosis.

The molecular mechanisms uncovered in 2023 read like a catalog of tumor ingenuity. Cross-species single-cell transcriptomics identified five subtypes of cancer-associated fibroblasts and revealed that CD36-positive fibroblasts secrete macrophage migration inhibitory factor in response to lipid peroxidation, orchestrating immune evasion. Integrin alpha-v was shown to be cleaved by gamma-secretase into an intracellular domain that drives invasion, with fibroblast-derived periostin as the trigger. Researchers linked SLFN11 deficiency to infiltration by immunosuppressive macrophages, showed that the FGF19/FGFR4 axis elevates ETV4 to boost PD-L1 expression and myeloid infiltration, and found that lysine lactylation at position K28 disables adenylate kinase 2 to fuel proliferation. Even diet and circadian biology entered the picture: fructose-driven acetate from gut bacteria promoted tumor growth via O-GlcNAcylation, and hepatocellular carcinoma cells were shown to hijack the host’s clock proteins Bmal1 and Clock to proliferate and spread.

Resistance to immunotherapy is also yielding to scrutiny. A patient-derived organoid biobank of 65 models replicated the proteogenomic typing of original tumors and predicted drug responses with high precision, offering a route to personalized combination therapy. Tandem mass spectrometry revealed that immune checkpoint therapy itself catalyzes sialylation of immunoglobulin G antibodies, blunting type I interferon responses and weakening treatment, a mechanism with proposed reversal strategies. Immunosuppressive CD10-positive ALPL-positive neutrophils were found to drive irreversible T cell exhaustion, and matrix metallopeptidase 9 emerged as a key effector of CTNNB1-mutant tumors whose inhibition may restore CD8-positive T cell activity and sensitize disease to PD-1 blockade. Together, these findings sketch a future in which precision medicine, guided by multi-omics profiling and delivered through rational multimodal regimens, converts one of the world’s deadliest cancers into a manageable, and perhaps one day curable, disease.

Subject of Research: Clinical trials and basic research advances in hepatocellular carcinoma immunotherapy and tumor biology in China

Article Title: Advances in clinical and basic research for hepatocellular carcinoma in China: a 2023 review

Article References: Wang, P., Sun, Y., & Fan, J. (2024). Advances in clinical and basic research for hepatocellular carcinoma in China: a 2023 review. Clinical Cancer Bulletin, 3(1), Article 15. https://doi.org/10.1007/s44272-024-00019-7

Image Credits: AI Generated

DOI: 10.1007/s44272-024-00019-7

Keywords: hepatocellular carcinoma, liver cancer, immunotherapy, immune checkpoint inhibitors, neoadjuvant therapy, adjuvant therapy, transarterial chemoembolization, single-cell sequencing, spatial transcriptomics, tumor microenvironment, drug resistance, precision medicine