Local macrophage dynamics-inspired engineering of time-programmed nano-vaccine scaffold for postoperative cancer immunotherapy.

The spatiotemporal dynamics of macrophages during non-cancer wound healing have been extensively studied; however, the dynamics of tumour-associated macrophages (TAMs) in the local tumour microenvironment (TME) after tumour resection have received little attention. This study shows that after tumour resection in mice, the inflammatory phase dominated by M1-like TAMs at the wound only lasted for approximately 2 d, which is much shorter than the desired time, i.e., 7-10 d, for the body to establish effective anti-tumour immunity. Moreover, the antigen cross-presentation of M2-like TAMs does not occur spontaneously. Inspired by local macrophage dynamics, we developed a sustained-release cancer vaccine targeting M2-like TAMs, E64 encapsulated mannose modified hybrid membrane vesicle in gel (E@M-HMV in gel), that effectively reprogrammed the phenotype and antigen cross-presenting function of M2-like TAMs in the postoperative local TME. In mice with orthotopic triple-negative breast cancer primary or distal tumours, subcutaneous colon cancer, and subcutaneous hepatocellular carcinoma, the injection of vaccines into the tumour resection cavity could elicit robust tumour-specific immunity and long-term immune memory, thereby inhibiting tumour recurrence, postoperative lung metastasis, and further tumour re-challenge, especially when combined with an immune checkpoint blockade. Collectively, our study not only elucidates the changing pattern phenotype of TAMs in the postoperative TME but also provides a promising scenario for efficient tumour immunotherapy by harnessing local macrophages.