The immunotherapeutic effect elicited by photodynamic
therapy (PDT)
is attenuated by tumor defense mechanisms associated with glutamine
metabolism, including the metabolic regulation of redox homeostasis
and the limitation of the immunosuppressive tumor microenvironment
(ITM). Herein, a carrier-free immunotherapeutic nanobooster C9SN with
dual synergistic effects was constructed by the self-assembly of glutaminase
(GLS) inhibitor compound 968 (C968) and photosensitizer Chlorin e6.
C968-mediated GSH deprivation through inhibiting glutamine metabolism
prevented PDT-generated reactive oxygen species from being annihilated
by GSH, amplifying intracellular oxidative stress, which caused severe
cell death and also enhanced the immunogenic cell death (ICD) effect.
In addition, genome-wide analysis was carried out using RNA-sequencing
to evaluate the changes in cell transcriptome induced by amplifying
oxidative stress. Thereafter, neoantigens generated by the enhanced
ICD effect promoted the maturation of dendritic cells, thereby recruiting
and activating cytotoxic T lymphocytes (CTLs). Meanwhile, C9SN remodeled
the ITM by blocking glutamine metabolism to polarize M2-type tumor-associated
macrophages (TAMs) into M1-type TAMs, which further recruited and
activated the CTLs. Ultimately, this immunotherapeutic nanobooster
suppressed primary and distant tumors. This “kill two birds
with one stone” strategy would shed light on enhancing tumor
immunogenicity and alleviating tumor immunosuppression to improve
the immunotherapeutic effect of PDT.
Chemoresistance is a formidable issue in clinical anticancer
therapy
and is pertinent to the lowered efficacies of chemotherapeutics and
the activated tumor self-repairing proceedings. Herein, bifunctional
amphiphiles containing galactose ligands and high-density disulfide
are synthesized for encapsulating mitochondrion-targeting tetravalent
platinum prodrugs to construct a cascade targeted and mitochondrion-dysfunctional
nanomedicine (Gal-NP@TPt). Subsequent investigations verify that Gal-NP@TPt
with sequential targeting functions toward tumors and mitochondria
improved the spatiotemporal level of platinum. In addition, glutathione
depletion by Gal-NP@TPt appear to substantially inhibit the proceedings
of platinum detoxification, inducing the susceptibility to the mitochondrial
platinum. Moreover, the strategic transportation of platinum to mitochondria
lacking DNA repair machinery by Gal-NP@TPt lowers the possibility
of platinum deactivation. Eventually, Gal-NP@TPt demonstrates appreciable
antitumor effects for the systemic treatment of patient-derived tumor
xenografts of hepatocellular carcinoma. Note that these strategies
in overcoming drug resistance have also been confirmed to be valid
based on genome-wide analysis via RNA-sequencing. Therefore, an intriguing
multifunctional nanomedicine capable of resolving formidable chemoresistance
is achieved, which should be greatly emphasized in practical applications
for the treatment of intractable tumors.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.