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.