Objective: Evaluate xenograft survival and immune rejection after unilateral pig-to-Tibetan macaque penetrating keratoplasty (Xeno-PKP).  
Methods: Xeno-PKP was performed in four macaques using corneas from triple-gene knockout minipigs (GTKO/SdaKO/CMAHKO) with human transgenes (hCD55/TBM or hCD55). Recipients received subconjunctival triamcinolone postoperatively. Grafts were monitored by slit-lamp until rejection prompted enucleation and histopathology.  
Results: Early postoperative clarity was achieved in all grafts. By POD 8, grafts remained clear without leakage. Signs of rejection (keratic precipitates, neovascularization, fibrinous deposits) emerged in two recipients by POD 19. Universal diffuse stromal opacification, edema, and neovascularization occurred by POD 28. Histopathology confirmed T-lymphocyte–dominant rejection with mixed inflammatory infiltration (lymphocytes, plasma cells, macrophages, eosinophils). Structural abnormalities included irregular epithelium, posterior stromal adhesions, and stromal exudates. Neovascular density varied, with pronounced networks in two specimens.  

Conclusions: Gene-edited porcine corneas prevented hyperacute rejection but not chronic rejection in monkey recipients. Rejection drivers likely include:  
1. Donor-recipient corneal thickness disparity，
2. Neovascular invasion disrupting immune privilege，
3. Graft-iris adhesions compromising ACAIP，
4. Absence of systemic immunosuppression. While genetic modification is beneficial, excessive edits risk donor viability and introduce new antigenic exposures. Optimizing combinations of edits—rather than increasing edit number—is critical for prolonging graft survival. Xenogeneic endothelial grafts implanted in the anterior chamber may leverage immune-privileged microenvironments to enhance tolerance, representing a promising alternative to allografts.