<p>The efficacy of cancer immunotherapy is often limited by the failure to initiate and sustain a complete cancer-immunity cycle within the immunosuppressive tumor microenvironment (TME). To address this, we developed a co-delivery strategy that integrates an immunogenic cell death (ICD) inducer with the natural immunomodulator <i>Lycium barbarum</i> polysaccharide (LBP), wherein the ICD inducer promotes tumor antigen release to initiate immune priming, while LBP amplifies the response by enhancing dendritic cell maturation and reprogramming the TME. To implement this strategy, we constructed a biomimetic core–shell nanovaccine, BL@Ram, with efficient tumor-targeting capacity. It comprises a poly(lactic-co-glycolic acid) (PLGA) core co-encapsulating Brusatol and LBP, which is further cloaked with a macrophage membrane to confer immune evasion and inherent tumor tropism. This innate targeting is augmented by surface conjugation of cRGD peptides, enabling active targeting to α_vβ₃ integrin-overexpressing tumor vasculature and cells, thereby establishing a robust dual-targeting system. In an immunologically “cold” pancreatic tumor models, BL@Ram efficiently accumulated and triggered a coordinated immune response, leading to markedly enhanced cytotoxic T lymphocyte infiltration. When combined with αPD-1, the system achieved complete tumor regression in 30% of mice and significantly prolonged survival. Furthermore, by modularly substituting the ICD inducer, we developed analogous nanovaccines that showed broad efficacy in prostate cancer, breast cancer, melanoma, and colorectal cancer models. This work establishes a versatile nano-immunotherapy platform that orchestrates coordinated immune activation for synergistic and durable antitumor immunity.</p>