Alkaline Adjuvant Regulates Proteolytic Activity of Macrophages for Antigen Cross‐Presentation and Potentiates Radioimmunotherapy

Abstract Failures of radiotherapy (RT) in adaptive antitumor immunomodulation often associate with recruited tissue‐repairing macrophages. Although training these macrophages to phagocytose post‐RT cancer cells reverses their protumoral performance, engulfed tumor antigens are severely underrated. In fact, regulating the processing and presentation of tumor antigens, a key determinant of tumor immunogenicity, can fundamentally affect adaptive immune responses. Here it is reported that a simple Alum‐like adjuvant (MgAl‐based hydrotalcite, bLDH) improves radioimmunotherapy via inducing antigen cross‐presentation by macrophages, independent of phenotypes. It is identified that cytidine monophosphate guanosine oligodeoxynucleotide engenders macrophages to phagocytose irradiated cancer cells. However, as semiprofessional antigen‐presenting cells, macrophages possess powerful proteolytic function that is detrimental to antigen presentation. The administration of alkaline bLDH intriguingly relieves the activity of phagolysosomal proteases with acidic pH optima by preventing phagosomal acidification resulting from the vacuolar‐type ATPase proton pump. The adjuvant‐modulated phagolysosomes thus limit antigen degradation and enhance tumor antigen cross‐presentation over tenfold. To examine from an in vivo breast tumor model, trained macrophages successfully cross‐prime antigen‐specific CD8 + T cells and curb RT‐associated metastasis. The findings propose to pay close attention to the effect of adjuvants on precision immunotherapy and highlight the positive contribution of cross‐presenting macrophages in radioimmunotherapy.