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Page 22 of 33 Mao et al. Chem Synth 2023;3:26 https://dx.doi.org/10.20517/cs.2022.41

As depicted in Figure 14A, the latest trials involving the combination of Cu chalcogenides-based
multimodality were discussed . In the following, we will briefly describe methods to further improve this
[184]
collaborative therapy, such as achieving image-guided collaborative therapy, promoting penetration into the
deep part of the tumor, and enhancing ROS induced in the TME. Zhou et al. reported a Cu Se@PtSe (CSP)
2-x
nano-sensitizer that resembled a yolk-shell structure was enhanced by the HIF-1α inhibitor acriflavine
(ACF), as shown in Figure 14B. It alleviated tumor hypoxia and blocked the G2/M phase to enhance the
radiosensitivity; moreover, it exhibited strong X-ray attenuation due to its high-Z element composition,
thereby enhancing the radiotherapy effect on the mouse breast cancer model . It demonstrated the
[185]
excellent potential of the resultant functional nano-sensitizers of tumor radiotherapy. Peng et al. prepared
the high-Z element-based hollow mesoporous TaOx nanospheres with the following growth of ultrasmall
CuS nanocrystals. Then they packaged with O saturated perfluoropentane (PFP), named
2-
HMTCP@PFP@O 2 . It exhibited prominent PTT efficiency, well biocompatibility, the ability to
[186]
concentrate the energy of irradiation, and the capacity to carry strong oxygen. Therefore, it can be used for
tumor RT, as shown in Figure 14C. A spindle-shaped CuS@CeO core-shell nanoparticles were synthesized
2
by Jiang et al., which simultaneously combined self-oxygen supply, photothermal ability, and
radiosensitization, as shown in Figure 14D . CeO -encapsulated CuS nanoparticles can be stably released
[187]
2
and penetrate deep into the tumor, thereby reducing the effect of radiotherapy on lesion regression.
Moreover, it has shown that the design not only reduces the radiotherapy dose but, more importantly, treats
the entire tumor without recurrence.

Immunotherapy
The diagnosis and therapy of cancer have been extensively discussed in the previous literature. One of the
main reasons for the failure of cancer treatment is tumor metastasis and recurrence. Immunotherapy, the
Nobel Prize in Physiology or Medicine of 2018, has brought hope and opportunity to address this issue.

Immunogenic cell death (ICD) was more likely to be induced by deep tumor penetrating ablation, resulting
in a more uniform distribution of released tumor antigens . Tumor PTT, as mentioned above, has
[189]
attracted more attention due to its advantages of low adverse reactions and non-invasiveness for cancer
treatment. However, the hyperthermia therapy strategy alone is still inadequate to inhibit tumor metastasis
and recurrence. Therefore, the combination strategy with Immunotherapy (IT) presents significant
therapeutic efficiency for malignant tumors, which opens a new avenue for cancer therapy.

Wang et al. developed a surface-functionalized CuS NP named CuS-PEG-Mal , which can be used not
[153]
only for tumor hyperthermia as photothermal media but also as an antigen-capture agent to adsorb tumor
antigens released during hyperpyrexia to induce anti-tumor immune responses. As shown in Figure 15A, an
immune checkpoint inhibitor was combined with anti-PD-L1 to evaluate the efficacy of CuS-mediated
hyperthermia in improving tumor immunotherapy through surface-functionalized modification. Yan et al.
reported a collaborative photothermal immunotherapy device for Cas9 riboprotein targeting PTPN2 based
on the CuS nanotherapeutic platform . HS-modified DNA (DNA-SH) chippings were coupled with CuS
[188]
and combined with Cas9 RNP via base complementary pairing methods. They are then coated with
endosomal destructive polyethyleneimine (PEI), as shown in Figure 15B, and named CuS-RNP@PEI (CRP).
It was endocytosed by cancer cells because of the modification of the cationic PEI on the surface of NPs.
After PEI-assisted endosomal escape, CRP was released into the cytoplasm and improved by photothermal
induction of double-strand breaks provided by NIR-triggered CuS, as shown in Figure 15C. Thus, this NIR
light-triggered therapy platform provides a multifunctional therapeutic strategy with a synergetic effect,
namely, “1 + 1 > 2”. What is more, for the combination of multimodal therapies described above, one of the
main challenges is developing an appropriate vector institution for efficient co-loading and targeted delivery