CDT
One of the most important aspects of CDT is the application of Fenton
reaction to the tumor microenvironment (TME) for cancer therapy[22].
In tumors, H2O2 overexpression and mild
acidity produce more cytotoxic hydroxyl radicals via Fenton and
Fenton-like reactions. CDT mediated by ROS has demonstrated a
significant anti-cancer effect without external stimulation or drug
resistance and is currently viewed as a promising treatment for
cancer[22, 29]. Numerous chemodynamic drugs, including nanomaterials
based on Fe2+, Cu+,
Mn2+, Mo4+, and
Ti3+, have been developed over time with improved CDT
efficacy[29]. However, the inability of a single CDT approach to
completely eradicate tumors paved the way for research into fresh system
designs for multimodal therapy and improved CDT. Hou et al.designed a transformable honeycomb-Like nano-assemblies of CDs, which
delivered doxorubicin, immunotherapeutic enhancer (Fe ions), and tumor
microenvironment modifier losartan[30] (Figure 2a). The drug-loaded
nano-assemblies firstly disassociated into individual CDs to release
losartan to mitigate stroma and hypoxia. And then, the individual CDs
carrying doxorubicin and Fe ion efficiently penetrated deep into tumor
to trigger intensified immune responses, including effective T cell
infiltration, tumor growth inhibition, and lung metastasis
prevention[30]. A carbon quantum dots (CQDs)-based biocompatible
nanozyme made from chlorogenic acid (ChA), a significant bioactive
natural component from coffee, was reported by Yaoet al [31]. They
discovered that ChA CQDs had blatant GSH oxidase-like behaviors and
consequently encouraged ferroptosis in cancer cells by interfering with
GPX4-catalyzed lipid repair mechanisms[31]. ChA CQDs significantly
reduced the tumor growth in HepG2-tumor-bearing mice in vivo and
attracted large numbers of immune cells that infiltrated the tumor, such
as T cells, NK cells, and macrophages, turning “cold tumors” into
“hot tumors” that triggered systemic anti-cancer immune
responses[31] (Figure 2b). Moreover, He et al. used a
DA-CQD@Pd single atom nanozyme (SAN) and immune adjuvant CpGODN to
create a bioadhesive injectable hydrogel for localized immunomodulation
and catalysis-augmented immunotherapy[32]. The SAN, which has high
water dispersibility, was made by adding Pd single atoms to a DA-CQD
support[32]. Due to a dual catalytic mechanism, the DA-CQD@Pd SAN
displayed excellent catalytic activity. The inherent catalytic activity
of a single Pd atom, which can catalyze the conversion of
H2O2/APS to hydroxy radicals
(•OH), is one aspect. The other
is the catechol-quinone redox pairs on the DA-CQD that catalyze the
production of •OH from H2O2/APS as
well[32] (Figure 2c). Noteworthily, the SAN converted
H2O2 into hydroxyl radicals, causing
immunogenic cell death (ICD) in tumors and producing tumor-associated
antigens in the tumor lysate, which triggered an immune response against
the tumor[32]. In addition, solvothermal-produced photoactivatable
Pt(IV)-coordinated CDs (Pt-CDs) and their bovine serum albumin (BSA)
complex (Pt-CDs@BSA) were created by Guo et al [33] (Figure
2d). In comparison to pure Pt-CDs, Pt-CDs@BSA exhibit expanded particle
sizes of 50–120 nm, which have significantly increased cellular
absorption and tumor accumulation. Under orange light, these materials
effectively reduce Pt(IV) to Pt(II) and encourage the generation of
•OH from water. Due to effective
cytotoxic Pt(II) species release, •OH formation, and intracellular
acidification, this novel approach with ultra-strong cancer cell killing
capacities produced substantially stronger in vivo ICD than
cisplatin at the same Pt dose. Pt-CDs@BSA treatment not only destroyed
the main tumor but also inhibited distant tumor growth and lung
metastasis, showing improved antitumor and antimetastatic
activity[33]. Together, these studies indicate that the synergistic
use of CDT and immunotherapy become one of the most popular cancer
treatments in recent years.
Vaccine
Tumor
vaccine therapy is designed by
introducing tumor antigens into the patient to stimulate a specific
anti-tumor immune response and improve the immune microenvironment[34,
35]. Due to its advantages of tumor specificity and long maintenance
time in vivo, vaccine therapy has become a popular research field in
cancer therapy[24, 34]. The vaccine can be divided into therapeutic
vaccines and preventive vaccines[36]. Therapeutic vaccines have
significantly different characteristics from traditional preventive
vaccines[36]. It needs to be designed and engineered to gain the
ability for tumor-specific treatment[24]. Luo et al.synthesized a CD with citric acid and PEG-1500 as the vaccine adjuvants
to be combined with the tumor protein antigen model ovalbumin
(OVA)[37]. The combination of CDs and OVA (CDs-OVA) could accelerate
antigen uptake and maturation of dendritic cells (DCs). After CDs-OVA
treatment, the expression of costimulatory molecules CD80 and CD86 of
DCs was increased, which subsequently stimulated splenocyte
proliferation and the production of interferon-gamma (IFN-γ). In vivo,
CDs-OVA also induced strong antigen-specific cellular immune responses
to inhibit the growth of B16-OVA melanoma cancer in C57BL/6
mice[37]. Different chiral precursors may produce CDs with different
properties. Another study by Liu et al. reported a chiral CD that
was synthesized from citric acid and L/D glutamic acid and then bound to
antigen model OVA[38] (Figure 3a). Compared to the L-OVA, D-OVA
could be effectively internalized by DCs, boost DC maturation,
cross-present antigen to T cells, and suppress the growth of B16-OVA
melanoma[38] (Figure 3b). In conclusion, these works exhibit the
high potential of CDs as the vaccine for tumor inhibition and
immunotherapy.
Immunoadjuvant
Unlike vaccines, immunoadjuvants are not antigenic, which is used to
increase tumor immunogenicity or enhance the immune response of immune
cells in cancer[34]. Thus, immunoadjuvants are often used in
conjunction with some immunotherapies, such as PD-1/PD-L1
blockers[34]. CDs have been increasingly applicated in
immunoadjuvants in recent years[39]. Liet
al. reported a nanoparticle prepared by the supramolecular assembling
of CDs and Ricin toxin binding subunit B (RTB)[40]. The formed
CDs-RTB can protect RTB against enzymatic hydrolysis, promote macrophage
proliferation, and increase inflammatory cytokines secretion in
macrophages[40]. CDs themselves also have the ability to play as
immunoadjuvants. Cow manure-derived CDs were reported can induce many
necrocytosis and inflammatory infiltrates in tumors, which suggested the
potential of CDs as an immune therapy adjuvant[41]. In addition,
Arezkiet al. used citric acid and branched polyethyleneimine to
synthesize a kind of cationic CDs that can induce inflammasome-dependent
pyroptosis via lysosomal dysfunction[42]. It is worth noting that
pyroptosis could induce the release of tumor cell antigens and recruit a
large number of immune cells[42, 43]. Further, as the
immunoadjuvants, the target of CDs is not only cancer cells. Zhouet al. reported that mannose-derived CDs (named as Man-CDs) could
effectively capture several “danger signals” after microwave ablation
treatment and then deliver these signals specifically to dendritic cells
(DCs)[44]. In vivo, intratumoral injection of Man-CDs stimulated a
potent tumor-specific immune response and suppressed both primary and
distant tumors[44]. All of these studies demonstrated that CDs could
be effective adjuvants that enhance tumor-specific immunotherapy.