Reactivating necroptosis in colorectal cancer potentiates chemotherapy and antitumor immune responses

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• Necroptosis, a form of immunogenic cell death (ICD), is often lost in cancer, limiting therapeutic options.
• Restoring necroptosis in cancer therapy is challenging due to the lack of agents that selectively induce necroptosis over apoptosis.

Purpose of the Study:

• To investigate strategies for restoring necroptosis in RIP3-silenced colorectal cancer (CRC) cells to enhance chemosensitivity.
• To evaluate the efficacy of the natural compound OSW-1 in combination with 5-fluorouracil (5-FU) for CRC treatment.

Main Methods:

• Investigated RIP3 reconstitution and RIP3-independent necroptosis induction using OSW-1 in CRC cells.
• Assessed the synergistic effects of OSW-1 and 5-FU on cell killing, necroptosis, and apoptosis.
• Analyzed the molecular mechanisms, including p53 and CaMKIIδ involvement in MLKL phosphorylation.
• Evaluated immunogenic cell death hallmarks and immune infiltration in vitro and in vivo models, including patient-derived organoids.

Main Results:

• Reconstituting RIP3 did not improve chemotherapy efficacy.
• OSW-1 effectively induced RIP3-independent necroptosis and showed strong synergy with 5-FU in eliminating RIP3-silenced CRC cells and tumors.
• The OSW-1/5-FU combination induced immunogenic cell death, increased immune infiltration in tumors, and its anti-tumor effect was dependent on CD8+ T cell immunity.
• Combination therapy enhanced immune infiltration in patient-derived CRC organoid models.

Conclusions:

• OSW-1 represents a promising strategy to activate RIP3-independent necroptosis, overcoming impaired necroptosis in CRC.
• The OSW-1/5-FU combination enhances CRC cell killing and boosts anti-tumor immunity, offering a novel therapeutic approach.