Immune Evasion Strategies of Human Poxviruses: A Roadmap for Engineering Low-Immunogenic CAR-Based and iPSC-Derived Cell Products

Allogeneic chimeric antigen receptor (CAR)-based cell products and induced pluripotent stem cell (iPSC)-derived regenerative grafts increasingly use multilayer immune engineering. Current strategies are strongest against direct human leukocyte antigen (HLA)-dependent recognition but incompletely address natural killer (NK)-cell counter-pressure, priming by recipient antigen-presenting cells, humoral and complement-mediated injury, inflammatory remodeling, blood- and tissue-interface damage, and terminal cell killing. Poxvirus research has characterized diverse immunomodulatory mechanisms relevant to these barriers. We review poxviral control of interferon signaling, antigen processing and presentation, T-cell activation, NK-cell surveillance, cytokine and chemokine networks, complement, inflammatory signaling, and regulated cell death, integrating viral mechanisms with human perturbation, cell-engineering, and transplantation evidence. A qualitative Tier 1–3 framework distinguishes mechanisms close to current cell-therapy practice from those requiring greater product-specific validation or control. The resulting design rules favor graded antigen-presentation control with paired NK validation, local or transient inflammatory buffering, interface-restricted complement protection, and survival enhancement only when independent eliminability is preserved. Selected poxviral proteins can act autonomously outside productive infection, but direct viral-protein expression remains a selective rather than default option. We propose a conditional defense-in-depth framework in which modules are added only when a residual barrier is demonstrated in the final therapeutic product.