Liver cancer, particularly hepatocellular carcinoma (HCC), remains one of the deadliest cancers, driven by high recurrence and resistance to therapy. Scientists are increasingly turning to an unexpected ally—PANoptosis, a newly identified form of programmed cell death that integratesthe features of apoptosis, pyroptosis, and necroptosis. Unlike conventional approaches, PANoptosis unleashes both direct tumor-killing effects and powerful immune activation, making it a promising strategy for tackling tumors that have developed resistance to standard treatments. By mapping the genetic signatures, cellular pathways, and therapeutic targets of PANoptosis, researchers are opening new doors to early diagnosis, tailored therapies, and improved survival outcomes for patients with this challenging disease.
HCC exerts a heavy global toll, especially in regions where hepatitis B and other liver diseases remain prevalent. Despite the success of vaccines and antiviral drugs, lifestyle-related risk factors such as obesity, diabetes, and fatty liver disease are fueling a new wave of cases. Current treatment options—ranging from surgery, chemotherapy, and targeted therapy to emerging immunotherapies—often fall short, as tumors recur or develop resistance. At the heart of this problem is the tumor microenvironment, which suppresses immune defenses and shields cancer cells from destruction. Due to these persistent challenges, researchers are now focusing on PANoptosis to uncover new ways of diagnosing, predicting, and treating liver cancer, particularly HCC.
A research team from Zhejiang University and Kunming Medical University has taken a bold step into uncharted territory, publishing (DOI: 10.20892/j.issn.2095-3941.2025.0150) the first comprehensive review of PANoptosis in HCC. Released in Cancer Biology & Medicine on July 8, 2025, the study explores how this hybrid form of cell death reshapes the liver tumor microenvironment and enhances immune defenses. By synthesizing the latest findings from molecular biology, genetic profiling, and experimental therapies, the authors outline how PANoptosis could revolutionize both diagnostics and treatment for liver cancer.
At the center of this emerging field is the PANoptosome, a molecular platform that orchestrates signals from apoptosis, pyroptosis, and necroptosis. Unlike traditional single-pathway mechanisms, PANoptosis sparks a chain reaction: rupturing tumor cells, releasing inflammatory molecules like IL-1β and IL-18, and summoning immune cells into action. In liver cancer, this dual impact—direct tumor cell killing and immune reprogramming—positions PANoptosis as a potent therapeutic tool. Studies reveal that activating PANoptosis boosts the activity of dendritic cells, CD8+ T cells, and natural killer cells, thereby transforming an immunosuppressive tumor niche into an immune-responsive one. Genetic models further show that PANoptosis signatures can divide patients into groups with distinct responses to chemotherapy and immunotherapy, allowing for tailored treatment. Cutting-edge experiments go a step further: for example, the enzyme DNASE1L3 was found to trigger PANoptosis during drug treatment, while Bi2Sn₂O₇ nanozymes activated by ultrasound successfully amplified tumor cell death and halted metastasis. Together, these findings suggest that PANoptosis could serve not just as a biomarker but as a cornerstone for personalized medicine in HCC.
"PANoptosis is rewriting the rules of how we think about cell death in cancer," said Dr. Yang Ke, co-lead author of the study. "Its ability to integrate multiple death pathways while simultaneously reawakening the immune system makes it uniquely powerful against tumors that resist standard therapies. For HCC, where recurrence and immune evasion are so common, this approach offers a real chance to change outcomes. The challenge ahead is to translate these discoveries into clinical tools that can benefit patients as swiftlyas possible."
The potentialof PANoptosis extends far beyond the laboratory. Genetic and molecular markers linked to this pathway could provide earlier, more accurate predictions of disease progression, giving doctors a clearer roadmap for treatment. Therapies that deliberately induce PANoptosis—whether through engineered enzymes, nanomaterials, or drug combinations—may overcome the stubborn resistance seen in advanced liver cancer. By combining artificial intelligence with PANoptosis signatures, researchers also envision more precise patient stratification and treatment planning. Looking ahead, clinical trials that integrate these strategies could usher in a new era of precision oncology, where harnessing the body's own cell death machinery becomes a powerful weapon against liver cancer.
