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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