Targeting Tumor Microenvironment in Liver Cancers: Rationale, Current Progress, and Future Perspective

Area of Science:

• Hepatobiliary and Pancreatic Oncology
• Translational Cancer Research

Background:

• Surgical resection offers curative potential for liver cancers but is often not feasible due to unresectable disease at diagnosis or post-surgical progression.
• Limited efficacy of existing local and systemic treatments for advanced hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and metastatic pancreatic ductal adenocarcinoma (PDAC) results in poor survival rates.

Purpose of the Study:

• To review recent advancements in oncology offering renewed hope for patients with advanced liver cancers.
• To highlight the potential of novel therapeutic strategies, including hypofractionated radiation, antiangiogenic agents, chemotherapy, and immunotherapy, in managing unresectable liver malignancies.
• To emphasize the need for further research into combination therapies and early-stage interventions for improved patient outcomes.

Main Methods:

• Review of current and emerging treatment modalities for advanced liver cancers.
• Discussion of clinical trials and preclinical studies investigating novel therapeutic approaches.
• Emphasis on a "bench to bedside and back" translational research strategy.

Main Results:

• Hypofractionated radiation shows promise in unresectable HCC and is under investigation in a Phase III trial.
• Antiangiogenic agents (sorafenib, lenvatinib, regorafenib, cabozantinib, ramucirumab) have significantly impacted advanced HCC management.
• Immunotherapy (anti-PD-1/PD-L1, anti-CTLA4) demonstrates potential in both first- and second-line settings for advanced HCC.
• Chemotherapy remains the standard of care for ICC and PDAC.

Conclusions:

• Combination strategies involving novel agents hold promise for durable and profound responses in advanced HCC.
• Further mechanistic preclinical studies and correlative clinical trial validation are crucial for optimizing combination therapies.
• Translational research is key to developing effective targeted agents in combination and for earlier disease stages, aiming to improve survival for aggressive liver cancers.