αTIGIT-guided IL-15 mimetics drive potent and safe antitumor immunity by restoring tumor-infiltrating T cells.

αTIGIT-guided IL-15 mimetics significantly enhance antitumor activity and safety by targeting tumor-infiltrating lymphocytes in vivo.

• Why it matters: Cytokines' clinical application is hindered by instability, toxicity, and poor drug-like properties, limiting their therapeutic potential in cancer treatment.
• What they did: Researchers engineered bispecific IL-15 mimetics using phage display, AlphaFold3 structural screening, and comparative format testing, identifying potent tandem IL-15R agonists, and incorporated anti-TIGIT antibodies to target TILs, creating a tri-antibody design.
• The result: The αTIGIT-αIL-15Rβγ mimetics improved antitumor activity, increased intratumoral stem-like T cells, and showed no detectable systemic toxicity even at high doses, suggesting a safer, more effective cytokine immunotherapy approach.