Contribution and Impact

Hepatocellular carcinoma (HCC) remains one of the deadliest cancers worldwide, with more than 800,000 deaths each year. For patients with chronic hepatitis B virus (HBV) infection, the risk is especially acute: up to half of all HCC cases are HBV-driven. Despite this immense burden, therapeutic options remain limited, and detection is often too late for curative treatment. As Dr. Chari Cohen of the Hepatitis B Foundation emphasized in our interview, "The #1 concern for people living with chronic hepatitis B is liver cancer and the mortality associated with it. The fear related to liver cancer is underappreciated in the medical community." This fear reflects a critical gap in medicine: the lack of tools that can provide both early intervention and safe, targeted treatment.

Our project addresses this gap by introducing a therapeutic strategy that is both selective and programmable. By requiring simultaneous detection of two independent disease signals before therapy is activated, our system achieves exceptional specificity while reducing collateral damage to healthy tissue — a major limitation of current treatments such as chemotherapy or checkpoint inhibitors, which act systemically and cause toxic side effects. This advance matters both for its modularity and wide applicability: safer, more specific therapies mean patients can be treated earlier, more effectively, and with fewer debilitating consequences.

Equally important, our approach leverages the unique biology of HBV-HCC. More than 90% of hepatocytes in HBV-HCC tumors carry integrated HBV DNA, which get transcribed in RNA that serve as a flag for viral infection. Alone, these transcripts are not valid therapeutic triggers, as they're present in non cancerous HBV-infected tissue as well. By pairing them with an endogenous HCC biomarker through our AND-gate design, we convert this variability into therapeutic precision. The result is a therapeutic switch that is both disease-specific and broadly applicable across patients.

This innovation advances the field of HCC therapy in three key ways:

1. Precision at the molecular and cellular level: by requiring simultaneous detection of two RNA signals, our logic gate achieves a level of selectivity that surpasses conventional single-biomarker approaches.

2. Modularity for future therapies: the system can be adapted to drive apoptosis using proteins and antibodies, opening the door to personalized and next-generation treatments.

3. A platform beyond HCC: while we focus on HBV-HCC as a proof of concept, the same framework could be extended to other cancers or diseases where multiple non-specific biomarkers exist but none are sufficient alone.

For patients, the impact is life-changing and deeply meaningful: therapies that no longer force them to choose between cancer progression and toxic side effects, but instead offer precise, programmable, and safe interventions. Most importantly, for the field, this project introduces a new paradigm in cancer therapy: one that transforms the problem of imperfect biomarkers into an opportunity for logic-based precision medicine.