Fueling IgA‐Dominated Humoral Immunity with an Intranasal Hybrid Tumor Vaccine to Opsonize and Strike Epithelial Breast Cancer

Abstract Humoral immunity‐cancer crosstalk has gained attention recently owing to its impact on tumor immune responses and therapy responsiveness. Here, it is shown that epithelial breast cancer cells can directly bind with non‐antigen‐specific IgA, dependent on polymeric immunoglobulin receptor (PIGR)‐mediated transcytosis function, modulating tumoral inflammatory genes and sensitizing antitumor response. To harness this biology, a hybrid tumor vaccine is designed by covering the adjuvant‐loaded cancer cell vesicles with a calcium phosphate shell, which retains the antigen information of the original tumor cells and exhibits robust mucosal adhesion in nasal tissues. Following intranasal vaccination, such a hybrid vaccine preferentially activates germinal center responses in nasal‐associated lymphoid tissues and drives the production of tumoral antigen‐specific IgA‐dominated humoral immunity in both serum and lung through the property of “common mucosal immune system”, thus coordinating cellular immune responses to prevent lung colonization of IgA‐opsonized breast cancer. In the inoperable and postoperative breast cancer model, intranasal vaccination with the hybrid vaccine also enables the amplification of the therapeutic benefits of local/systemic therapies. In summary, this work presents insights into the antitumor biology of IgA in epithelial breast cancer and explores a highly effective vaccine strategy focused on governing IgA‐dominated humoral immunity to combat breast cancer, especially lung metastasis.