Tumor surgery can create an inflammatory trauma to aggravate residual tumor “seed” to colonize pre-metastatic niches (PMNs) “soil” at secondary sites, thereby promoting post-operative metastasis. However, two-pronged strategies for post-surgical elimination of asynchronous “seeds” and “soil” at different regions are currently lacking. Here, we have designed a hydrogel that can be injected into a resection cavity, where it immediately forms a scaffold and gradually degrades responding to enriched reactive oxygen species at adjacent trauma for local delivery and on-demand release of autologous cancer cells succumbing to oncolysis (ACCO) and anti-inflammatory agent. The autologous cell source self-provides a whole array of tumor-associated antigens, and the oncolysis orchestration of a subcellular cascade confers a self-adjuvanting property, together guaranteeing high immunogenicity of the ACCO vaccine that enables specific antitumor immunization. In parallel, inflammation alleviation exerted bidirectional functions to reshape the local immune landscape and resuscitate ACCO, leading to the eradication of residual tumor “seeds” while simultaneously intercepting the “seed–soil” crosstalk to normalize distant lung leading to regression of pre-existing PMN “soil”. As a result, regional and metastatic recurrence were completely thwarted. Together, this framework synchronizing oncolysis immunization and inflammation alleviation provides an effective option for post-operative suppression of metastasis.

The endoplasmic reticulum (ER) in cancer cells has been considered as a pharmacological target. Still, the effects of a ER‐targeted system remain less investigated, due to the fact that most chemo‐drugs take actions in the nucleus. Here, it is demonstrated that ER‐targeted delivery of doxorubicin (DOX), a typically nucleus‐tropic‐and‐acting agent, attenuates its original effect on cytotoxicity while generating new functions favorable for immune activation. First, a library of DOX derivatives with variable ER‐targeting abilities is synthesized. The results reveal that higher ER‐targeting efficiency correlates with greater ER stress. As compared with naïve drug, ER‐targeted DOX considerably alters the mode of action from nuclear DNA damage‐associated cytotoxicity to ER stress‐mediated calreticulin exposure. Consequently, ER‐targeted DOX decreases cytotoxicity but increases the capability to induce immunogenic cell death (ICD). Therefore, a platform combining naïve and ER‐targeted DOX is constructed for in vivo application. Conventional polymer‐DOX conjugate inhibits tumor growth by exerting a direct killing effect, and ER‐targeted polymer‐DOX conjugate suppresses residual tumors by eliciting ICD‐associated immunity, together resulting in considerable tumor regression. In addition, simultaneous inhibition of adaptive PD‐L1 enrichment (due to negative‐feedback to ICD induction) further leads to greater therapeutic outcome. Collectively, ER‐targeted therapy can enhance anticancer efficacy by promoting ICD‐associated immunotherapy, and potentiating chemotherapy and checkpoint blockade therapy.

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As the foremost cause of cancer‐related death, metastasis consists of three steps: invasion, circulation, and colonization. Only targeting one single phase of the metastasis cascade may be insufficient since there are many alternative routes for tumor cells to disseminate. Here, to target the whole cascade of metastasis, hybrid erythrocyte and tumor cell membrane‐coated nanoparticle (Hyb‐NP) is designed with dual functions of increasing circulation time and recognizing primary, circulating, and colonized tumors. After loading with monensin, a recently reported metastasis inhibitor, the delivery system profoundly reduces spontaneous metastasis in an orthotopic breast cancer model. Underlying mechanism studies reveal that Hyb‐NP can deliver monensin to its action site in the Golgi apparatus, and in return, monensin can block the exocytosis of Hyb‐NP from the Golgi apparatus, forming a reservoir‐like subcellular structure. Notably, the Golgi apparatus reservoir displays three vital functions for suppressing metastasis initialization, including enhanced subcellular drug retention, metastasis‐related cytokine release inhibition, and directional migration inhibition. Collectively, based on metastasis cascade targeting at the tissue level, further formation of the Golgi apparatus drug reservoir at the subcellular level provides a potential therapeutic strategy for cancer metastasis suppression.

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