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.