Figure 6. (a) The chemical structures of Lac-PEG-b-PLys(Ad), DCTBT, and CD-NO. (b) Schematic illustration of the supramolecular nanocarrier T-SPMDCTBT/NO for ONOOˉ-potentiated mild-temperature PTT of hepatocellular carcinoma. (c) Detection of intracellular NO, ROS, and ONOOˉ by fluorescent microscopy after LM3 cells with different treatment. (d) The heat map of HSP-related proteins for LM3 cells with different treatment. (e) The expression of HSP90 in tumor tissues was measured by Western blot after different treatments. (f) The quantitative analysis of relative HSP90 expression based on the Western blot results. (g) The tumor volumes at different time intervals. Reproduced from Ref. [188] with permission. Copyright 2023 Wiley-VCH.
However, the single use of MPTT also faces the problems of not completely killing the entire tumor tissue, damage to the surrounding normal tissue, and biological safety of photothermal materials. To solve the limitations of MPTT monotherapy, a series of combination therapies based on MPTT have been widely studied, including chemotherapy, PDT, gene therapy and immunotherapy. As one of the traditional methods of cancer treatment, chemotherapy is widely used in clinical practice, but it is limited by insufficient local drug concentration, serious adverse reactions, and drug resistance.[5, 189, 190] Chemotherapy-loaded nanomaterials can effectively solve the above problems through passive targeting of EPR or active targeting of surface-bound molecules. Moreover, local heating during photothermal therapy can also improve the permeability of cell membrane and the cytotoxicity of drugs, and achieve ”1+1>2 ”of efficacy. Zhang et al. introduced a copper (Cu)-palladium (Pd) alloy tetrapod NPs (TNP-1) as a solution to the challenges of chemo-MPTT. TNP-1 NPs exhibit superior PCE, primarily attributed to their distinctive sharp-tip structure. Interestingly, these NPs induce pro-survival autophagy in a manner dependent on their shape and composition. The inhibition of autophagy using compounds like 3-methyl adenine or chloroquine has a remarkable synergistic effect when combined with TNP-1-mediated MPTT. This synergy was demonstrated in triple-negative (4T1), drug-resistant (MCF7/MDR), and patient-derived breast cancer models.[191] This approach utilized autophagy inhibitors instead of traditional chemotherapeutic agents, offering a promising strategy for eradicating drug-resistant cancers. The results presented in this study provide a proof-of-concept for a chemo-MPTT strategy that has the potential to overcome drug resistance effectively. Shao et al. developed a multifunctional rattle-structured nanoparticle with a core of PDA and a shell of hollow mesoporous silica (PDA@hm). The central cavity of PDA@hm can load the autophagy inhibitor drug chloroquine (CQ) to form PDA@hm@CQ. Additionally, the surface of the mesoporous silica shell is conjugated with glucose oxidase (GOx), creating a corona-like structure (PDA@hm@CQ@GOx). This system presented a strategy that combined MPTT with the modulation of cell energy metabolism and autophagy inhibition. The self-polymerized PDA nanocore, derived from dopamine monomers, serves as the photothermal conversion agent for MPTT and as a contrast agent for PAI in vivo. GOx enhanced glucose depletion, leading to the suppression of HSP70 and HSP90 expression, thus enhancing the MPTT effect. Furthermore, autophagy inhibition by CQ further enhanced the therapeutic effects with minimal toxicity.[192] This approach offers a promising strategy for effective cancer therapy. Chen et al. developed a multifunctional nanotherapeutic platform based on CuS that responds to NIR light for controlled release of CRISPR-Cas9 ribonucleoprotein (RNP) and DOX, enabling a combination therapy approach involving gene therapy, MPTT, and chemotherapy. The controlled release of gene-editing materials and drugs is achieved through the formation of double strands between CuS-linked DNA fragments and single-guide RNA in response to photothermal stimulation. Cas9 RNP targeted Hsp90α to reduce the tumor’s heat tolerance, enhancing the effects of MPTT. The combination therapy, involving two rounds of NIR light irradiation, demonstrated significant synergistic efficacy compared to MPTT alone.[193] This externally controlled approach offers a versatile strategy for controlled gene editing and drug release, with the potential for synergistic combination therapy. Chen et al. developed a biocompatible and intelligent nanoplatform based on benzothiazole-linked conjugated polymer NPs (CPNs). This nanoplatform was designed to efficiently load DOX and Mo-based polyoxometalate (POM) through dynamic chemical bonds and intermolecular interactions, creating a novel anticancer drug with multiple responsive capabilities to the TME and external laser irradiation. The controlled release of DOX from the resulting nanoformulation (CPNs-DOX-PEG-cRGD-BSA@POM) can be triggered by both endogenous factors (such as GSH and low pH in the TME) and external laser irradiation, as demonstrated through pharmacodynamic studies. Furthermore, the inclusion of POM in the nanoplatform not only enabled MPTT but also promoted self-assembly behavior in the acidic TME, leading to enhanced tumor retention. Thanks to its versatile functions, CPNs-DOX-PEG-cRGD-BSA@POM exhibited excellent tumor targeting and therapeutic effects in murine xenografted models, demonstrating significant potential for practical cancer therapy.[194] Xiong et al. developed a novel nanodrug delivery system (NDDS) using mesoporous polydopamine (mP) as both a drug carrier and a photothermal generator. This system was designed to deliver Olaparib (Ola), an FDA-approved PARP inhibitor, and DOX to treat breast cancers. The study addressed the limitation of PARP inhibitors, which are effective primarily in breast cancers with homologous recombination (HR) deficiency. Additionally, the abnormal mechanical microenvironment of breast cancers often hinders drug transport to tumor cells. In this innovative approach, locally applied MPTT, effectively inhibiting the HR repair pathway by downregulating key HR-related proteins, including MRE11, RAD51, and BRCA2. Simultaneously, MPTT could reduce cancer-associated fibroblasts (CAFs) and alleviate hypoxia, leading to a decrease in the dense extracellular matrix (ECM) of breast cancer.[195] This reduction in ECM normalized tumor mechanics and vasculature, facilitating the delivery and penetration of drugs. As a result, the NDDS induced potent DNA damage, enhancing antitumor efficacy with a significant tumor inhibition rate of 86.1%, while minimizing systemic side effects. The study not only underscores the potential of MPTT-induced HR deficiency in clinical cancer therapy but also sheds light on the mechanisms of MPTT in inhibiting DNA damage repair and regulating tumor mechanics.
Tumor immunotherapy can activate the body’s own defense system to identify, attack and destroy tumor cells, which has been the focus of research in recent years.[126, 196-198] It has been reported that the thermal effect of tumors can release tumor-associated antigens (TAAs), which can be recognized by dendritic cells (DCs) and presented to T cell receptors with the help of immune adjuvants to activate immune responses. MPTT can change the tumor microenvironment by activating the systemic immune response, increasing the infiltration of tumor T cells, and turning ”cold” tumors into ”hot” tumors, thereby enhancing the efficacy of anti-PD-L1 antibody (aPD-L1) on immune checkpoint blockade (ICB). Duan et al. developed a cascade synergistic immunotherapy nanosystem, referred to as CpG@PDA-FA, to enhance the anticancer immune response. This nanosystem combined PDA with the immunomodulator CpG oligodeoxynucleotides (CpG ODNs) that lead to ICD to activate DCs and enhance the antitumor immune response of T cells. In addition to PTT, CpG ODNs play a crucial role in promoting the maturation and migration of DCs while ameliorating the immunosuppressive TME. This dual action of CpG ODNs complements the effects of MPTT induced by PDA.[199] The study demonstrated that CpG@PDA-FA achieved a remarkable synergistic treatment effect compared to single MPTT or CpG therapy. This effect was observed in the maturation of DCs and activation of T cells. Furthermore, CpG@PDA-FA reduce myeloid-derived suppressor cells and regulatory T cells, which helps alleviate immunosuppression. Overall, CpG@PDA-FA provided a bidirectional immunotherapy strategy for tumor inhibition, highlighting the cascade effects of MPTT and immunotherapy. This innovative approach held promise for enhancing the efficacy of cancer immunotherapy. Wang et al. developed a novel approach called ”Matthew Effect Photoimmunotheranostics (MEP)” that utilizes an intelligent proton-driven enhanced nanoconverter (PEN) with self-refueling capacity. This system was designed for MPTT and immunotherapy. The PEN was created through a simple polymerization method using the biocompatible photothermal agent polyaniline (PANI) combined with glucose oxidase (GOx) as an enhancer. When intravenously injected, the PEN selectively accumulates in the tumor region. GOx, presented in the PEN, depleted glucose within the tumor, creating an energy shortage and increasing acidity in TME. This unique combination of factors works in synergy. It suppresses the expression of heat shock proteins in tumor cells, disrupting their thermoresistance mechanisms. Simultaneously, it promotes the proton-driven conversion of PANI into its activated state.[200] Remarkably, the PEN can bidirectionally differentiate between normal and cancerous tissues, operating in an ”OFF-ON-OFF” mode. This ability minimized adverse effects by capitalizing on the significant difference in glucose consumption between normal cells and tumor cells. The hyperthermia induced by PEN can lead to ICD. When combined with PAI and NIR-II light irradiation, PEN achieves tumor elimination with high specificity, generating a synergistic effect of mild hyperthermia and immune response through MEP. Furthermore, the PEN-induced adaptive antitumor immunity was effective at eliminating distant tumors, suppressing tumor metastasis, and preventing recurrence. Overall, MEP represented an innovative and promising approach for cancer therapy that combines MPTT, immunotherapy, and advanced imaging techniques to achieve highly specific and effective tumor treatment. Ran et al. introduced a novel approach called ”rhythm MPTT” using organic photothermal NPs (PBDB-T NPs). This technique aimed to enhance tumor elimination and induce ICD, ultimately promoting tumor-specific immune responses for effective tumor treatment. PBDB-T NPs offered several advantages, including biocompatibility, precise and controllable photothermal properties, and the ability to serve as noninvasive diagnostic imaging agents. They also demonstrated potent performance in MPTT against oral squamous cell carcinoma (OSCC). One of the key findings is the temperature-dependent release of DAMPs during MPTT-induced ICD. This process involved the controlled generation of DAMPs because of precise temperature modulation during treatment. The concept of ”rhythm MPTT” involved orchestrating the MPTT procedure in a manner like radiotherapy (Figure 7).[201] This approach amplifies and balances the antitumor efficiency with the generation of abundant DAMPs, aiming to achieve optimal immune activation. Importantly, this is done within the clinically recommended hyperthermia temperature range, which distinguished it from conventional PTT. Both in vitro and in vivo experiments demonstrated that rhythm MPTT effectively combined the tumor-killing effect with the induction of ICD, resulting in strong MPTT efficacy and the activation of tumor-specific adaptive immune responses. This study introduced a promising strategy that opens new avenues for the clinical application of MPTT, offering a potential breakthrough in cancer treatment.