Zoledronic acid/cisplatin-loaded cucurbit[7]uril-modified upconversion nanoformulations drive tumor-associated macrophage polarization and potentiate the efficacy of cancer immunotherapy

Tumor-associated macrophages (TAMs) play a pivotal role in establishing a tumor immunosuppressive microenvironment (TIME) by inducing a phenotypic shift in macrophage from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. This polarization facilitates tumor growth, progression, metastasis, immune evasion, and chemoresistance. Consequently, reprogramming the TIME by repolarizing TAMs has emerged as a promising approach in cancer therapy. In this study, we synthesized core-shell structured nanoparticles (UCNPs@CB-Zol-Pt) utilizing host-guest interactions between NaYF₄:Yb/Er (UCNPs) and cucurbit[7]uril (CB). These nanoparticles were designed to polarize M2-like macrophages into M1-like macrophages and release tumor-associated antigens (TAAs), thereby potentially inducing the release of immunogenic cell death (ICD). Furthermore, the M1-type macrophages could ingest, process, and present TAAs generated from platinum-based chemotherapy through MHC class II molecules. This process simultaneously enhances the infiltration of helper and effector T cells into the TIME, thereby potentiating the efficacy of checkpoint blockade immunotherapy.