Engineered nano-aluminum adjuvant for cancer immunotherapy: Progress, challenges and opportunities towards preclinical/clinical application

Immunotherapy is a promising strategy to inhibit the progression of solid tumors. However, current vaccine adjuvants represented by aluminum adjuvant (Alum) fail to adjuvant tumor antigens to initiate effective T cell immunity. Despite efforts have been made to optimize the physical characteristics of Alum, the lack of specific immunostimulatory functions still results in their inability to effectively induce cytotoxic T cell immune responses. Encouragingly, an iterative layered double hydroxide (LDH) nano‑aluminum adjuvant (NanoAlum) re-engineered from clinical AlOOH Alum and Mg(OH)2 antacid has shown promising efficacy in evoking both potent humoral and cellular immunity. Notably, it can also serve as an microenvironmental immunomodulator to reshape the aberrant physicochemical attributes of the tumor microenvironment. Interestingly, the highly flexible crystal structure and chemical composition offer a variety of LDH-based candidates (NanoMAlum) by doping with body essential nutritional metal ions (M), which show great potential to amplify tumor immunotherapy. In this review, we summarize the development and progress of LDH NanoAlum and its variants NanoMAlum for cancer immunotherapy. By rethinking the challenges that have hindered the preclinical/clinical application, we have charted a research pathway based on engineered organoids to accelerate the clinical applications of these LDH NanoAlum and NanoMAlums in this review.