Cancer is one of the leading causes of human death, despite enormous efforts to explore cancer biology and develop anticancer therapies. The main challenges in cancer research are establishing an efficient tumor microenvironment in vitro and exploring efficient means for screening anticancer drugs to reveal the nature of cancer and develop treatments. The tumor microenvironment possesses human-specific biophysical and biochemical factors that are difficult to recapitulate in conventional in vitro planar cell models and in vivo animal models. Therefore, model limitations have hindered the translation of basic research findings to clinical applications. In this review, we introduce the recent progress in tumor-on-a-chip devices for cancer biology research, medicine assessment, and biomedical applications in detail. The emerging tumor-on-a-chip platforms integrating 3D cell culture, microfluidic technology, and tissue engineering have successfully mimicked the pivotal structural and functional characteristics of the in vivo tumor microenvironment. The recent advances in tumor-on-a-chip platforms for cancer biology studies and biomedical applications are detailed and analyzed in this review. This review should be valuable for further understanding the mechanisms of the tumor evolution process, screening anticancer drugs, and developing cancer therapies, and it addresses the challenges and potential opportunities in predicting drug screening and cancer treatment.

A high rate of recurrence after curative therapy is a major challenge for the management of hepatocellular carcinoma (HCC). Currently, no effective adjuvant therapy is available to prevent HCC recurrence. We designed a personalized neoantigen-loaded dendritic cell vaccine and neoantigen-activated T-cell therapy, and used it as adjuvant therapy to treat 10 patients with HCC who had undergone curative resection or radiofrequency ablation in the first stage of a phase II trial (NCT03067493). The primary outcomes were safety and neoantigen-specific immune response. Disease-free survival (DFS) was also evaluated. The immunotherapy was successfully administered to all the patients without unexpected delay and demonstrated a reasonable safety profile with no grade ≥3 treatment-related side effects reported. Seventy percent of patients generated de novo circulating multiclonal neoantigen-specific T-cell responses. Induced neoantigen-specific immunity was maintained over time, and epitope spreading was observed. Patients who generated immune responses to treatment exhibited prolonged DFS compared with nonresponders (P = 0.012), with 71.4% experiencing no relapse for 2 years after curative treatment. High expression of an immune stimulatory signature, enhanced immune-cell infiltration (i.e., CD8+ T cells), and upregulated expression of T-cell inflammatory gene profiles were found in the primary tumors of the responders. In addition, neoantigen depletion (immunoediting) was present in the recurrent tumors compared with the primary tumors (7/9 vs. 1/17, P = 0.014), suggesting that immune evasion occurred under the pressure of immunotherapy. Our study indicates that neoantigen-based combination immunotherapy is feasible, safe, and has the potential to reduce HCC recurrence after curative treatment.

Radiofrequency ablation (RFA) kills tumor cells by generating heat using a high-frequency alternating current. The heat leads to coagulative necrosis in tumorous and adjacent liver parenchymal cells. RFA is currently considered as a curative treatment in selected patients with hepatocellular carcinoma (HCC). During the past few decades, studies comparing therapeutic effectiveness of RFA with surgical resection have been conducted.^1-3 RFA is now established as a first-line therapy for very early and early HCC according to the Barcelona Clinic Liver Cancer treatment strategy⁴ because of its excellent effectiveness, minimal invasiveness, and convenient availability. However, as tumor size increases, HCC recurrence after RFA becomes more common than after liver resection.⁵ Large tumors are known to associate with higher incidences of adjacent microvascular invasion and micrometastases, important contributing factors to recurrence after HCC treatment.⁶ Thus, RFA can only be used to treat small tumors as the extent of RFA in destroying the tumor and its adjacent surrounding tissues is limited. The other reason for the high recurrence rate after RFA is that heating can result in an increase in intratumoral pressure, which can displace and diffuse tumor cells through iatrogenic arterioportal fistula or intratumoral shunt created around the ablated zone.^7-9

Background and Aims: Systemic treatments are listed as first-line therapies for HCC with portal vein tumor thrombus (PVTT), resulting in modest efficacy. We aimed to evaluate the efficacy and safety of sintilimab plus bevacizumab combined with radiotherapy in HCC with PVTT and to identify prognostic biomarkers. Approach and Results: This open-label, multicenter, single-arm, phase 2 clinical trial was conducted at 3 tertiary hospitals in China. A total of 46 patients with HCC with PVTT were enrolled. All the patients received the first cycle of i.v. sintilimab (200 mg, day 1) plus bevacizumab (15 mg/kg, day 1) within 3 days after enrollment. Radiotherapy (30–50 Gy/10 fractions) was administered after 2 cycles of Sin-Bev. Sin-Bev was disrupted during radiotherapy and resumed 2 weeks after radiotherapy and continued every 3 weeks thereafter until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was objective response rate. Patients obtained an objective response rate of 58.7% and a disease control rate of 100%. After a median follow-up time of 26.0 months (95% CI: 24.0–26.0), the median OS was 24.0 months (95% CI: 19.0 to not applicable) and the median progression-free survival was 13.8 months (95% CI: 12.0–21.0), respectively. No unexpected adverse events or treatment-related deaths occurred. Mutations of PCTMD1 were predictive of shorter OS and progression-free survival. Conclusions: Sintilimab plus bevacizumab combined with radiotherapy provides favorable treatment response and survival outcomes along with an acceptable safety profile in the first-line setting for patients with HCC with PVTT (ClinicalTrials.gov Identifier: NCT05010434).