T-cell memory, tumor microenvironment, and alloreactivity in intracellular neoantigen–targeted immunotherapy

Advances in genetic engineering have transformed cancer immunotherapy, enabling the development of T-cell–based and antibody-based strategies that target intracellular neoantigens. In particular, TCR-engineered T cells and TCR-mimic antibodies recognizing peptide–MHC complexes have expanded the range of targetable tumor antigens beyond surface proteins. This Perspective outlines a conceptual framework in which three interacting but context-dependent biological axes–T-cell memory differentiation, tumor microenvironment (TME) regulation, and control of alloreactivity–collectively determine therapeutic efficacy and safety. While T-cell memory and TME-mediated suppression broadly influence the persistence and function of engineered T-cells, graft-versus-host disease (GVHD) represents a distinct challenge restricted to allogeneic settings. Emerging evidence highlights the importance of memory T-cell subsets, particularly stem-like and central memory populations, in sustaining long-term antitumor immunity. However, their function is frequently constrained by immunosuppressive cellular networks and metabolic barriers within the TME, including regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. In parallel, advances in graft engineering and T-cell receptor editing provide strategies to mitigate alloreactivity while preserving graft-versus-tumor effects. By integrating these dimensions, this Perspective emphasizes the need for coordinated therapeutic strategies that balance durability, immune tolerance, and microenvironmental adaptation. A deeper mechanistic understanding of these interactions will be critical for the rational design of next-generation immunotherapies targeting intracellular tumor antigens.