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.