Whole‐Component Antigen Nanovaccines Combined With aTIGIT for Enhanced Innate and Adaptive Anti‐tumor Immunity

Abstract Using entire tumor cells or tissues that display both common and patient‐specific antigens can potentially trigger a comprehensive and long‐lasting anti‐tumor immune response. However, the limited immunogenicity, low uptake efficiency, and susceptibility to degradation of whole‐component antigens present significant challenges. In this study, we employed tumor lysates (TLs) as whole‐component antigens, in conjunction with MgAl‐layered double hydroxide (MA) as nanoadjuvants and Mn 2+ as immunostimulants, to create personalized MMAT (Mn 2+ ‐MA‐TLs) nanovaccines. After subcutaneous injection of MMAT nanovaccines, the high local concentrations of TLs and Mn 2+ facilitated the recruitment and activation of antigen‐presenting cells (APCs), thereby inducing a robust adaptive immune response. Remarkably, MMAT nanovaccines enabled lysosomal escape, enhanced antigen cross‐presentation, and activated the cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) pathway in APCs. Furthermore, MMAT nanovaccines, when combined with the anti‐TIGIT monoclonal antibody (aTIGIT), an immune checkpoint inhibitor, not only stimulated T‐cell‐based adaptive anti‐tumor immune responses but also activated the NK‐cell‐based innate anti‐tumor immunity, effectively suppressing tumor growth, recurrence, and metastasis. Thus, the ternary MMAT nanovaccines developed here introduced a pioneered paradigm for the rapid preparation of whole‐component tumor antigens with nanoadjuvants and immunostimulants into nanovaccines, offering new prospects for clinical immunotherapies.