Some organic small-molecule-based nanoparticles with strong NIR-II absorbance and excellent photothermal conversion efficacy have been constructed for NIR-II PTT combinational immunotherapy. In a recent study of our group, 3,3′,5,5′-tetramethylbenzidine (TMB)-based liposome nanocomplexes with pH-responsive NIR-II photothermal properties were constructed for combinational immunotherapy [52]. Thermal-responsive liposomes containing an amphiphilic polymer, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) (DSPE-PEG), and thermal-responsive 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), with a transition temperature of 41 °C, were synthesized to load pH-sensitive charge-transfer nanoparticles as the NIR-II photothermal agent, deoxyribonuclease I (DNase I), and stimulants of the natural killer (NK) cell (SIS3). Charge-transfer nanoparticles were transformed from TMB and exhibited a stronger absorption in the NIR-II window in an acidic environment relative to neutral and basic conditions and thus have pH-sensitive NIR-II photothermal properties [53]. Such nanocomplexes exerted a NIR-II PTT effect under 1064 nm laser irradiation (1.0 W/cm², 6 min) in a tumor acidic microenvironment, resulting in the increase of tumor temperature at around 45 °C. This destroyed the thermal-responsive liposomes to allow the on-demand release of SIS3 and DNase I. Due to the toxicity of DNase I, cancer cells were killed, and ICD was induced to promote immune responses. The action of SIS3 could synergize with DNase I-mediated ICD to promote the activation of NK cells and CD8⁺ cytotoxic T lymphocytes (CTLs). Thus, such a combinational immunotherapy could effectively inhibit the growth of primary and distant 4T1 tumors and completely prevented lung metastasis in subcutaneous mouse models.

The combination of reactive oxygen species (ROS) and NIR-II PTT-mediated heat generation for ICD induction and the promotion of immunotherapy has also been reported. As shown in Zhao’s group, small-molecule-based organic metal adjuvants (OMAs) with NIR-II photothermal properties and ROS-generating ability were developed for cancer therapy [55]. Such OMAs were constructed through the supramolecular assembly of commercially available donors and acceptors, showing excellent NIR-II photothermal properties and photoacoustic imaging performance via optimizing the constituting components. In a tumor microenvironment, OMAs oxidized cysteine and glutathione (GSH) to inhibit the biosynthesis of GSH, resulting in the disruption of redox homeostasis and boosting ROS accumulation inside cells. Under 1064 nm laser irradiation (1.0 W/cm², 5 min), OMAs exerted an NIR-II PTT effect to ablate cancer cells. In addition, the PTT effect and ROS generation mediated ICD induction with improved efficacy to enhance the immune response by promoting the maturation of dendritic cells (DCs) and the infiltration of T cells. Such an ROS-generating NIR-II PTT could be combined with anti-programmed cell death protein 1 (aPD-1) antibody-mediated immune checkpoint blockade therapy to allow for the increased infiltration of T cells into tumor tissues, leading to the eradication of primary tumors and the significant inhibition of distant tumor growth in 4T1 tumor-bearing-mouse models.

To boost ROS generation for combining NIR-II PTT and immunotherapy, Shen’s group reported an “all-in-one” hydrogel for cancer treatment [56]. Such hydrogels were formed by loading ink as the NIR-II photothermal agent, HY19991 as the PD-L1 inhibitor, and an azo-initiator of 2,2-azobis [2-(2-imidazoline-2-acyl)propane]dihydrochloride (AIPH) into alginate hydrogels in situ crosslinked with Ca²⁺. Under 1064 nm laser irradiation (0.5 W/cm², 10 min), the ink exerted NIR-II PTT to increase the local temperature at around 45 °C, leading to the upregulation of PD-L1 expression and the formation of a large number of alkyl radicals from AIPH. The formed alkyl radicals augmented the ICD effect and increased the recruitment of tumor-infiltrating lymphocytes into tumors via the hydrogel-mediated conversion of “cold” tumors into “hot” tumors. Moreover, hydrogels released HY19991 to block the binding between PD-L1 and PD-1 to further improve the antitumor immunity. As a result, such “all-in-one” hydrogels could afford synergistic action via a mild PTT effect to reverse the tumor immunosuppressive microenvironment and triggered both innate and adaptive immune responses in CT26 tumor-bearing-mouse models, leading to the effective elimination of tumors and the prevention of distant metastatic tumors.

SPNs, as a class of optical materials transformed from semiconducting polymers (SPs) with excellent optical properties and biocompatibility, have also been used for NIR-II PTT and thus can mediate NIR-II PTT combinational immunotherapy [57,58,59]. To enhance the therapeutic efficacy of SPNs, Zhang and Pu’s groups developed a polymer multicellular nanoengager for synergistic NIR-II photothermal immunotherapy [60]. The nanoengager consisted of NIR-II-absorbing SPs as the photothermal agents and the surface camouflaged cell membranes derived from DCs and immunologically engineered tumor cells serving as the cancer vaccine shells. Such a design enabled multicellular engagements among T cells, DCs, and tumor cells, resulting in the enhanced activation of DCs and T cells. These nanoengagers could effectively accumulate into both lymph nodes and tumor tissues after systemic administration and acted as nanovaccines to trigger the immune response. Under 1064 nm laser irradiation (1.0 W/cm², 10 min), the nanoengagers exerted NIR-II PTT to eradicate tumors and induce ICD for further eliciting antitumor T cell immunity. The nanoengager-mediated NIR-II PTT synergistic immunotherapy not only efficiently inhibited the growth of both primary and distant 4T1 tumors and eliminated tumor recurrence but also triggered immunological memory for long-term immune surveillance.

By using thermo-responsive linkers, Pu’s groups reported an activatable polymer nanoagonist for the NIR-II photothermal immunotherapy of cancer [62]. The nanoagonists were constructed by covalently conjugating R848 onto NIR-II-absorbing SPNs via a labile thermo-responsive linker. Under 1064 nm laser irradiation (1.0 W/cm², 10 min), the nanoagonists exerted NIR-II PTT for killing tumor cells and inducing ICD. The generated heat also destroyed thermo-responsive linkers to achieve the on-demand release of R848 even in deep solid tumor tissue. The antitumor immune response in 4T1 tumor-bearing-mouse models was potentiated due to the combinational action of the NIR-II PTT-mediated ICD effect and R848-mediated TLR activation. Therefore, through the combinational action of NIR-II PTT and immunotherapy, these nanoagonists not only almost completely eradicated the primary tumors after direct laser irradiation but also obviously inhibited the growth of distant tumors and suppressed lung and liver metastasis.

In another study, Pu and coworkers reported a NIR-II light-activatable polymeric nanoantagonist for photothermal immunometabolic cancer therapy [63]. The polymeric nanoantagonist was obtained by conjugating an adenosine A2A receptor antagonist (vipadenant) onto NIR-II-absorbing SPs via the thermo-responsive linkers. Under 1064 nm laser irradiation (1.0 W/cm², 10 min), SPNs within nanoantagonists mediated NIR-II PTT to induce tumor thermal ablation and subsequently ICD, and the release of vipadenant through triggering the cleavage of the thermo-responsive linkers. The released vipadenant could block the binding between extracellular adenosine with A2A receptors on the surface of the CTLs and the regulatory T (T_reg) cells, thus promoting the priming and infiltration of CTLs but suppressing the functions of the T_reg cells to achieve an enhanced antitumor immune response. Such a combinational action of NIR-II PTT and immunotherapy, which was mediated by these nanoantagonists, allowed for the complete eradication of primary 4T1 tumors, the effective inhibition of metastasis, and the prevention of tumor relapse after reinoculation.

3. Inorganic Non-Metal Nanomedicines for NIR-II PTT Combinational Immunotherapy