The crosstalk between tumor and stroma cells is a central scenario in the tumor microenvironment (TME). While the predominant effect of tumor cells on immune cells is establishing an immunosuppressive context, tumor cell death at certain conditions will boost antitumor immunity. Herein, we report a rationally designed tumor specific enhanced oxidative stress polymer conjugate (TSEOP) for boosting antitumor immunity. The TSEOP is prepared by Passerini reaction between cinnamaldehyde (CA), 4-formylbenzene­boronic acid pinacol ester, and 5-isocyanopent-1-yne, followed by azide–alkyne click reaction with poly­(l-glutamic acid)-graft-poly­(ethylene glycol) monomethyl ether (PLG-g-mPEG). Under tumor stimuli condition, CA and quinone methide (QM) are quickly generated, which cooperatively induce strong oxidative stress, immunogenic tumor cell death (ICD), and activation of antigen presenting cells. In vivo studies show that the TSEOP treatment boosts tumor-specific antitumor immunity and eradicates both murine colorectal and breast tumors. This study should be inspirational for designing polymers as immunotherapeutics in cancer therapy.

Using nanotechnology for improving the immunotherapy efficiency represents a major research interest in recent years. However, there are paradoxes and obstacles in using a single nanoparticle to fulfill all the requirements in the complicated immune activation processes. Herein, a supramolecular assembled programmable immune activation nanomedicine (PIAN) for sequentially finishing multiple steps after intravenous injection and eliciting robust antitumor immunity in situ is reported. The programmable nanomedicine is constructed by supramolecular assembly via host–guest interactions between poly‐[(N‐2‐hydroxyethyl)‐aspartamide]‐Pt(IV)/β‐cyclodextrin (PPCD), CpG/polyamidoamine‐thioketal‐adamantane (CpG/PAMAM‐TK‐Ad), and methoxy poly(ethylene glycol)‐thioketal‐adamantane (mPEG‐TK‐Ad). After intravenous injection and accumulation at the tumor site, the high level of reactive oxygen species in the tumor microenvironment promotes PIAN dissociation and the release of PPCD (mediating tumor cell killing and antigen release) and CpG/PAMAM (mediating antigen capturing and transferring to the tumor‐draining lymph nodes). This results in antigen‐presenting cell activation, antigen presentation, and robust antitumor immune responses. In combination with anti‐PD‐L1 antibody, the PIAN cures 40% of mice in a colorectal cancer model. This PIAN provides a new framework for designing programmable nanomedicine as in situ cancer vaccine for cancer immunotherapy.

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Surgical resection is the first‐line therapy for colorectal cancer (CRC). However, for advanced CRC, the curative effect of surgical resection is limited due to either local recurrence or distal metastasis. Postoperative in situ immunotherapy, presents a promising option for preventing tumor recurrence and metastasis, owing to the fact that surgeons have unique opportunities and direct access to the surgical site. Herein, a designed biopolymer immune implant for CRC post‐surgical therapy, characterized with tissue adhesion, sustained drug release, and sequential elicitation of innate immunity, adaptive immunity, and immune memory effects, is reported. With gradual release of the loaded resiquimod (R848) and anti‐OX40 antibody (aOX40), the immune implant can eradicate residual tumors post‐surgery (with no tumor recurrence in 150 days), inhibit the growth of distal tumors and elicit immune memory effects to resist tumor re‐challenge. Immunological analysis reveal that the biopolymer immune plant treatment leads to a two‐stage action, with enhanced natural killer cells (NK cells) infiltration and activation of dendritic cells (DCs) in the first several days, then a greatly increased population of infiltrating T cells, and finally immune memory effects are established. The reported biopolymer immune implants provide a valuable and clinically‐relevant option for post‐surgical CRC management.

Tumor-promoting inflammation is accompanied by cancer initiation, progression, and metastasis. Cyclooxygenase-2 (COX-2) and its downstream product, prostaglandin E2 (PGE2), play critical roles in tumor-promoting inflammation. Several studies have revealed the potential of COX-2 inhibition in improving cancer response to chemotherapy, as well as immunotherapy. Aspirin, a nonsteroidal anti-inflammatory drug, has been reported as a COX-2 inhibitor. However, as a small molecule drug with a carboxyl group, there is still the lack of effective methods of preparing polymer-aspirin conjugates with tumor stimuli-responsive release properties. Herein, we synthesized a reactive oxygen species (ROS)-responsive aspirin polymeric prodrug (P3C-Asp) via Passerini three-component reaction between aspirin, 4-formylbenzeneboronic acid pinacol ester, and 5-isocyanopent-1-yne, followed by copper (I)-catalyzed alkyne-azide cycloaddition "click" reaction of the aspirin prodrug with dextran (DEX). The P3C-Asp could release aspirin and salicylic acid in response to tumor-specific stimuli. In the murine colorectal cancer model, P3C-Asp suppressed tumor growth effectively without significant side effects and eradicated tumors when combined with the immune checkpoint inhibitor, anti-PD-1 antibody (aPD-1). Further analysis revealed that the suppression was attributable to changes in the immune microenvironment, including reduced PGE2 content, as well as increased infiltration of CD8 + T cells and M1 macrophages. The results mentioned above proved that targeting COX-2 pathway with a proper polymeric prodrug might be a useful strategy for cancer immunotherapy.

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