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Immunotherapy has emerged as one of the major strategies for cancer treatment. Unlike conventional therapeutic methods, immunotherapy can treat both primary and distant metastatic tumors through triggering systematic antitumor immune responses and can even prevent tumor recurrence after causing the formation of immune memory. However, immunotherapy still has the issues of low patient response rates and severe immune-related adverse events in clinical practices. In this regard, the combination of nanomedicine-mediated therapy with immunotherapy can modulate a tumor immunosuppressive microenvironment and thus amplify antitumor immunity. In particular, second near-infrared (NIR-II) photothermal therapy (PTT), which utilizes light conversions to generate heat for killing cancer cells, has shown unique advantages in combining with immunotherapy. In this review, the recent progress of engineering nanomedicines for NIR-II PTT combinational immunotherapy is summarized. The role of nanomedicine-mediated NIR-II PTT in inducing immunogenic cell death and reprogramming the tumor immunosuppressive microenvironment for facilitating immunotherapy are highlighted. The development of NIR-II-absorbing organic and inorganic nonmetal and inorganic metal nanomedicines for the NIR-II PTT combinational immunotherapy of cancer is also introduced in detail. Lastly, the current challenges and future perspectives of these nanomedicines for combinational immunotherapy are proposed.

Immunotherapy is an attractive treatment strategy for cancer, while its efficiency and safety need to be improved. A dual-cascade activatable nanopotentiator for sonodynamic therapy (SDT) and chemodynamic therapy (CDT)-cooperated immunotherapy of deep tumors via reshaping adenosine metabolism is herein reported. This nanopotentiator (NP MCA ) is constructed through crosslinking adenosine deaminase (ADA) with chlorin e6 (Ce6)-conjugated manganese dioxide (MnO 2 ) nanoparticles via a reactive oxygen species (ROS)-cleavable linker. In the tumor microenvironment with ultrasound (US) irradiation, NP MCA mediates CDT and SDT concurrently in deep tumors covered with 2-cm tissues to produce abundant ROS, which results in dual-cascade scissoring of ROS-cleavable linkers to activate ADA within NC MCA to block adenosine metabolism. Moreover, immunogenic cell death (ICD) of dying tumor cells and upregulation of the stimulator of interferon genes (STING) is triggered by the generated ROS and Mn 2+ from NP MCA , respectively, leading to activation of antitumor immune response. The potency of immune response is further reinforced by reducing the accumulation of adenosine in tumor microenvironment by the activated ADA. As a result, NP MCA enables CDT and SDT-cooperated immunotherapy, showing an obviously improved therapeutic efficacy to inhibit the growths of bilateral tumors, in which the primary tumors are covered with 2-cm tissues.

Immunotherapy is an attractive approach for cancer therapy, while its antitumor efficacy is still limited, especially for non‐immunogenic tumors. Nanomedicines can be utilized to convert the non‐immunogenic “cold” tumors to immunogenic “hot” tumors via inducing immunogenic cell death (ICD), thereby promoting the antitumor immune response. Some nanomedicines that can produce local heat and reactive oxygen species upon the stimulation of electromagnetic energy are the main candidates for inducing the ICD effect. However, their applications are often restricted due to the poor tissue penetration depths of electromagnetic energy, such as light. By contrast, ultrasound, X‐ray, alternating magnetic field, and microwave show excellent tissue penetration depths and thereby can be used for sonodynamic therapy, radiotherapy, magnetic hyperthermia therapy, and microwave ablation therapy, all of which can effectively induce ICD. Herein, the combination of deep‐tissue electromagnetic energy with nanomedicines for inducing ICD and cancer immunotherapy are summarized. In particular, the designs of nanomedicines to amplify ICD effect in the presence of deep‐tissue electromagnetic energy and sensitize tumors to various immunotherapies will be discussed. At the end of this review, a brief conclusion and discussion of current challenges and further perspectives in this subfield are provided.

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