A study reports a discovery that opens up a new path into treating colorectal cancer (CRC), which is notoriously resilient, with chemoresistance and immunosuppression often standing in the way of effective treatments. Wuhan University scientists identified the mitochondrial protein TRAP1 as a key player in CRC’s defenses and disrupted its gene by developing an advanced oral CRISPR–Cas9 delivery system. Encased in nanocomplexes, this system navigates the gastrointestinal barriers to target tumors, triggering the destruction of cancer cells and activating immune responses. The result is enhanced chemotherapy effectiveness, reduced resistance, and a reshaped tumor immune response. This innovative approach yields promising preclinical results, paving the way for more effective and less invasive CRC therapies.

Boosting chemotherapy-induced cell death

Chemotherapy has shown promise in inducing immunogenic cell death (ICD) in tumor cells, boosting immune responses when combined with immune checkpoint blockade (ICB). Yet, variability in patient responses and widespread chemoresistance undermine outcomes, particularly in microsatellite-stable CRC. In a Nature Nanotechnology article, lead author Kai Zhao and colleagues identified mitochondrial stress, driven by proteins like TRAP1, as a key contributor to fostering chemoresistance and an immunosuppressive tumor microenvironment.

Since efforts to inhibit TRAP1 have faced technical challenges, Zhao and colleagues developed a novel oral CRISPR–Cas9 delivery system coated with trimethylamine oxide (TMAO)—a zwitterionic compound found in deep-sea fish known for its antifouling and protective properties—that offers a groundbreaking approach, overcoming digestive barriers and enhancing chemotherapy’s effectiveness in CRC treatment. The resulting oral CRISPR–Cas9 delivery system, called HTPBD (HA-TMAO-modified PBAE-based DNA vector), amplifies the effects of the chemotherapy drug 5-fluorouracil (5-FU), inducing a dramatic reduction in cancer cell viability. In vitro tests revealed significant mitochondrial damage, including swelling, cristae lysis, and elevated reactive oxygen species (ROS) levels, confirming the system’s potent chemosensitizing effects. Crucially, this combination treatment also triggered immunogenic cell death (ICD), a process that signals the immune system to attack the cancer cells.

To further validate these findings, the team used organoid models derived from ApcMin/+ mice, which closely mimic human tumors. HTPBDTRAP1 combined with 5-FU led to a notable reduction in organoid growth, reinforcing its role as a potent chemosensitizer. Moving to in vivo studies, the combination treatment showed remarkable tumor suppression in orthotopic CRC mouse models, achieving a 93.3% tumor inhibition rate, far surpassing the effects of standard monotherapies. Survival rates also improved dramatically, with treated mice living nearly twice as long as those in control groups.

HTPBDTRAP1 also demonstrated a favorable safety profile, with no significant adverse effects on vital organs or epithelial barrier function, making it a promising candidate for clinical applications. The system goes beyond simply enhancing chemotherapy; it also reshapes the tumor microenvironment (TME). Transcriptomic analysis revealed substantial changes in immune-related pathways, including the upregulation of pro-inflammatory cytokines and chemokines. Notably, the treatment led to an influx of immune cells, including cytotoxic CD8+ T cells and helper CD4+ T cells, while suppressive cells like regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) decreased significantly.

When used together with immune checkpoint blockade (ICB) agents like αPD-1, HTPBDTRAP1, and 5-FU showed strong ability to shrink tumors in hard-to-treat CRC models, successfully changing the immune-suppressing tumor environment into one that fights cancer. This synergy holds significant promise for enhancing the efficacy of both chemotherapy and immunotherapy.

Unleashing new possibilities for cold tumors

One of the most exciting aspects of this approach is its potential to tackle “cold tumors,” which lack immune infiltration and are resistant to current therapies. In genetically engineered ApcMin/+ mice, the combination of HTPBDTRAP1 and immunotherapy reduced tumor burden, eliminated detectable tumors, and promoted long-term survival, suggesting that this strategy could be key in treating even the most challenging cancer types. 

HTPBDTRAP1 exemplifies the potential of targeted gene editing and advanced drug delivery systems to revolutionize cancer treatment. By sensitizing tumors to chemotherapy and reshaping the TME, this innovative approach holds promise for overcoming drug resistance and enhancing immunotherapy outcomes. As the battle against CRC and other cold tumors continues, HTPBDTRAP1’s success underscores the importance of integrating cutting-edge technology with clinical ingenuity. This strategy paves the way for a new era of precision oncology, offering hope to patients who need it most.