Scientists at Wuhan University have unveiled a CRISPR-Cas9-based approach that not only delivers targeted gene editing through a groundbreaking oral system but also dismantles the cancer’s defenses, making tumors vulnerable to both chemotherapy and immunotherapy. This dual breakthrough, detailed in a recent study, offers new hope for patients with tough-to-treat colorectal cancer, especially the microsatellite-stable type that often defies standard therapies.
The therapy targets a mitochondrial protein called TRAP1, which fuels CRC’s ability to resist chemotherapy and suppress the immune system. To disrupt this protein, researchers developed HTPBD, a CRISPR-Cas9 delivery system encased in nanocomplexes and coated with trimethylamine oxide (TMAO). This innovative coating allows the therapy to navigate the digestive tract and hone in on tumors, overcoming a major hurdle for oral gene therapies. Once there, HTPBD disables the TRAP1 gene, stripping away the cancer’s protective shield.
When paired with the chemotherapy drug 5-fluorouracil (5-FU), HTPBD supercharges the drug’s effects, slashing cancer cell survival in lab tests by causing mitochondrial damage and spiking reactive oxygen species. It also triggers immunogenic cell death, a process that alerts the immune system to attack the tumor.

In mouse models mimicking human CRC, this combination achieved a remarkable 93.3% tumor suppression rate, far surpassing standalone treatments, and nearly doubled survival time. The therapy proved safe, with no significant harm to vital organs or gut barriers.

Beyond boosting chemotherapy, HTPBD transforms the tumor’s environment from a haven for cancer into a battleground for the immune system. It ramps up immune-friendly cells like cytotoxic T cells while reducing suppressive cells, paving the way for synergy with immunotherapy drugs like αPD-1. In challenging CRC models, this combo shrank tumors, eliminated detectable cancers in some cases, and promoted long-term survival. The therapy’s ability to tackle “cold tumors”—those that resist immune attack—marks it as a potential breakthrough for the toughest cases, but also for different kinds of cancer.

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