In recent years, cancer immunotherapy has fundamentally transformed the landscape of traditional cancer treatment by activating the body’s immune system to recognize and eliminate tumor cells. In particular, immune checkpoint blockade (ICB) therapies that target programmed death receptor-1 (PD-1)^[1], programmed death ligand-1 (PD-L1)^[2], and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)^[3] have demonstrated significant efficacy in treating various malignancies, including melanoma^[4,5], non-small cell lung cancer^[6], and renal cell carcinoma^[7]. At the same time, chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated unprecedented therapeutic potential in hematologic malignancies^[8] [Figure 1]. However, compared with hematologic malignancies, the complex biological characteristics and immunosuppressive microenvironment of solid tumors significantly limit the efficacy of immunotherapy, making it difficult for most patients to achieve durable clinical benefits.

Solid tumors typically exhibit a significantly immunosuppressive tumor microenvironment (TME), characterized by hypoxia^[9], an acidic metabolic environment^[10], abnormal vascular architecture^[11], and a dense extracellular matrix (ECM)^[12]. These factors not only hinder the penetration of drugs and immune cells into the deep layers of the tumor but also promote the accumulation of regulatory T cells (Tregs)^[13], myeloid-derived suppressor cells (MDSCs)^[14], and M2-type tumor-associated macrophages (TAMs)^[15], thereby creating a persistent state of immune suppression. Against this backdrop, many solid tumors exhibit a “cold tumor” phenotype characterized by a lack of effector T-cell infiltration, resulting in limited response to ICB therapy. Furthermore, CAR-T cells face challenges in solid tumors, including tumor antigen heterogeneity, low infiltration efficiency, and functional exhaustion^[16-18]. Therefore, overcoming the immune barriers in solid tumors and promoting tumor antigen release and immune cell recruitment have become key scientific challenges for improving the efficacy of cancer immunotherapy.

Advances in nanomedicine have opened up new opportunities for overcoming the immunosuppressive microenvironment of solid tumors. Thanks to their unique size-dependent effects and engineering flexibility, nanocarriers can enhance drug accumulation and retention at the tumor site, enabling the precise delivery of immunomodulators, chemotherapeutic agents, and nucleic acid drugs^[19-23]. At the same time, by integrating tumor microenvironment-responsive elements such as pH, reactive oxygen species (ROS), enzymes, and hypoxia, stimulus-responsive nanosystems can enable on-demand drug release and enhance local immune activation^[24-28]. In recent years, immuno-nanomedicine has gradually emerged. By deeply integrating nanotechnology with immunotherapy, it enables tumor antigen delivery, immune cell regulation, and tumor microenvironment remodeling^[14], demonstrating tremendous potential to improve treatment efficacy and reduce systemic toxicity^[29].

However, relying solely on tumor-endogenous stimuli is often limited by tumor heterogeneity and response efficiency, making it difficult to achieve precise spatiotemporal control^[30,31]. Therefore, the development of smart nanoplatforms that integrate exogenous stimulation strategies has become a current research focus. Among these, ultrasound - a noninvasive and clinically widely used form of physical stimulation - is attracting increasing attention due to its unique advantages^[32,33].

Ultrasound (US) is a mechanical wave with a frequency higher than 20 kHz that enables non-invasive energy delivery to biological tissues^[34,35]. Compared to exogenous stimulation methods such as light, magnetic fields, and electric fields, ultrasound has greater tissue penetration capability and can precisely target tissues at the centimeter level or even deeper, making it particularly suitable for the treatment of deep-seated solid tumors^[36-38]. Furthermore, focused ultrasound (FUS) technology can precisely concentrate ultrasound energy on the tumor region, providing excellent spatiotemporal controllability and enhancing treatment specificity while minimizing damage to normal tissues^[39-42].

At the biological level, ultrasound can induce various physical effects, such as thermal, mechanical, and cavitation effects, thereby enhancing tumor tissue permeability, promoting drug release, and regulating cellular behavior^[43-46]. Recent studies have shown that ultrasound is not only a physical therapeutic modality but also an important immunomodulatory tool. Ultrasound-induced cellular stress and tumor cell death can promote the release of tumor-associated antigens and activate the body’s immune system^[47-49]. At the same time, ultrasound can improve tumor vascular perfusion, reduce interstitial pressure, and enhance immune cell infiltration, thereby creating favorable conditions for subsequent immunotherapy^[50-52].

It is worth noting that ultrasound is already widely used in clinical diagnosis and treatment, including ultrasound imaging, high-intensity focused ultrasound (HIFU) ablation, and ultrasound-assisted drug delivery. This established foundation of clinical applications provides a significant advantage for translating ultrasound-based immunotherapy, giving it greater clinical potential than other emerging stimulation methods.

Advances in nanomedicine have further driven the evolution of ultrasound therapy from simple tumor ablation toward immune activation and immune regulation^[53]. By incorporating photosensitizers, piezoelectric materials, immunostimulants, and targeted delivery systems, ultrasound-responsive nanoplatforms can significantly amplify ultrasound-induced ROS production, tumor antigen release, and immunogenic cell death (ICD), thereby initiating the tumor immune cycle^[54-57]. At the same time, these nanoplatforms enable the precise delivery of immune checkpoint inhibitors, STING agonists, and cytokines, further enhancing ultrasound-induced antitumor immune responses^[58,59].

In recent years, a large body of research has confirmed that ultrasound-responsive nanoplatforms can not only induce local tumor regression but also promote dendritic cell maturation, enhance cluster of differentiation 8 (positive) (CD8⁺) T-cell infiltration, and establish long-term immune memory, thereby facilitating a transition from local therapy to systemic antitumor immunity^[54,60]. This shift in the research paradigm - from “tumor ablation” to “immune activation” and from “local treatment” to “systemic immunity” - is propelling ultrasound immunotherapy to become one of the most promising areas of development in the field of nanomedicine for cancer.

Tumor cell death is the initiating event by which ultrasound immunotherapy triggers the antitumor immune cycle. Unlike conventional therapies, which primarily induce a single apoptotic pathway, ultrasound stimulation can induce multiple forms of cell death, including apoptosis, necrosis, pyroptosis, ferroptosis, and necroptosis^[48,61]. Different modes of cell death exhibit varying degrees of immunogenicity, which in turn determine the intensity of subsequent immune activation.

Apoptosis is one of the most common forms of cell death in ultrasound therapy. Ultrasound activates photosensitizers, generating large amounts of ROS, which cause mitochondrial damage, the release of cytochrome C, and the activation of the caspase cascade, ultimately leading to programmed cell death^[62-64]. However, classical apoptosis is typically accompanied by the complete encapsulation and clearance of cellular contents, resulting in a mild inflammatory response. Therefore, its immunogenicity is relatively limited.

In contrast, ultrasound-induced necrosis can disrupt cell membrane integrity, resulting in the release of large amounts of intracellular components into the extracellular space. The released nucleic acids, proteins, and metabolic byproducts can be recognized by the body as danger signals, thereby inducing a local inflammatory response and the recruitment of immune cells^[65]. Although necrosis is highly immunogenic, its uncontrolled nature may damage normal tissues.

Recent studies have shown that inflammatory programmed cell death processes such as pyroptosis, ferroptosis, and necroptosis play an increasingly important role in ultrasound immunotherapy. Pyroptosis is a form of programmed inflammatory cell death mediated by Gasdermin proteins. Ultrasound-induced ROS can activate the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, promoting Caspase-1-mediated cleavage of Gasdermin D, which creates pores in the cell membrane and ultimately leads to the massive release of inflammatory factors such as interleukin-1 beta (IL-1β), interleukin-18 (IL-18), and ATP^[66-68]. Because pyroptosis is accompanied by a strong inflammatory response, it is considered a crucial bridge linking tumor cell death to immune activation.

Ferroptosis is a form of cell death that depends on iron ions and lipid peroxidation^[69]. Ultrasound-induced ROS promotes the accumulation of lipid peroxides and inhibits glutathione peroxidase 4 (GPX4) activity, thereby triggering ferroptosis^[70,71]. Studies have shown that the oxidized lipids and danger signals released during ferroptosis promote dendritic cell maturation and CD8⁺ T-cell infiltration, making it a subject of widespread interest in the field of tumor immunotherapy.

Necroptosis is a form of programmed cell death regulated by the RIPK1-RIPK3-MLKL signaling axis ^[72]. Compared with apoptosis, necroptosis releases more danger-associated molecular patterns (DAMPs) and induces a more intense immune response^[73]. A growing body of evidence suggests that ultrasound-induced necroptosis may be one of the key mechanisms for activating subsequent antitumor immunity.

Different types of cell death exhibit significant differences in immunogenicity, and their ability to induce antitumor immune responses varies. Recent studies have shown that programmed cell death pathways such as pyroptosis, necroptosis, and ferroptosis typically exhibit stronger immunostimulatory effects, while ultrasound-induced ICD is considered a crucial bridge linking localized tumor killing to systemic immune activation. A summary of the main characteristics and immunological effects of different cell death modes is presented in Table 1.

Among the various forms of cell death, ICD is considered a key bridge linking localized tumor killing to systemic immune activation. Unlike conventional forms of cell death, ICD not only eliminates tumor cells but also transforms the dead cells into natural “tumor vaccines,” thereby activating the body’s immune system.

The most important feature of ICD is the exposure and release of DAMPs. Among these, the exposure of calreticulin (CRT) on the cell surface is an early marker of ICD. As a typical “Eat-me signal,” CRT promotes the recognition and phagocytosis of dead tumor cells by dendritic cells and macrophages, thereby enhancing antigen uptake efficiency^[77]. At the same time, the release of extracellular ATP constitutes a “Find-me signal,” which recruits dendritic cells, macrophages, and neutrophils to the tumor site via purinergic receptor signaling pathways, thereby promoting the initiation of local immune responses^[78]. High-mobility group box protein 1 (HMGB1) is an important DAMP molecule released during the later stages of ICD^[79]. Upon binding to TLR4 on the surface of dendritic cells, HMGB1 promotes antigen processing and cross-presentation, thereby enhancing the efficiency of antigen-specific T-cell activation^[80]. Furthermore, the exposure of heat shock proteins heat shock protein 70(HSP70) and HSP90 also enhances tumor antigen presentation and immune recognition^[81].

In recent years, a large body of research has shown that ultrasound-responsive nanoplatforms can significantly enhance ICD through ROS bursts, endoplasmic reticulum stress, and mitochondrial damage. For example, the large amounts of ROS generated by sonodynamic therapy can induce an endoplasmic reticulum stress response, promoting CRT translocation and ATP release. Piezoelectric nanomaterials, in turn, can further amplify DAMPs release through sustained oxidative stress. Therefore, ICD is widely recognized as the core event that initiates the antitumor immune cycle in ultrasound immunotherapy.

DAMPs and tumor-associated antigens produced by ICDs further activate the body’s innate immune system, laying the foundation for subsequent adaptive immune responses. Dendritic cells (DCs) serve as a central hub linking the innate and adaptive immune systems. Upon stimulation by DAMPs, immature DCs gradually mature and upregulate the expression of CD80, CD86, and major histocompatibility complex (MHC) molecules, thereby enhancing their ability to process and present tumor antigens^[82,83]. However, DC metabolic dysregulation often leads to the premature transport of antigens to lysosomes for degradation, resulting in reduced antigen presentation efficiency, which severely limits the quality and intensity of T-cell activation. To address this bottleneck, Chen et al. developed an ultrasound-activatable in situ vaccine based on a thylakoid/platelet hybrid membrane-camouflaged nanovesicle (TPLHZ) that co-delivers the DNA methyltransferase inhibitor zebularine and the sonosensitizer hematoporphyrin monomethyl ether^[83]. Beyond boosting ROS-mediated ICD and antigen release, zebularine effectively reverses tumor DNA hypermethylation, upregulating MHC-I expression on tumor cells to enhance antigen self-presentation, while the ICD-triggered DAMPs synergistically promote DC maturation and cross-presentation. This dual-regulation strategy significantly amplifies T-cell activation, elicits potent cytotoxic CD8⁺ T-cell responses, establishes long-term immunological memory (characterized by increased central and effector memory T-cell populations), and demonstrates robust synergistic efficacy with immune checkpoint blockade, offering a promising approach to overcome anti-PD-1 resistance in solid tumors [Figure 2].

Tumor-associated macrophages (TAMs) are among the most abundant immune cells in the tumor microenvironment. In most solid tumors, TAMs primarily exhibit a pro-tumor M2 phenotype. Studies have shown that ultrasound-induced ROS and inflammatory factors can promote the conversion of M2 macrophages to M1 macrophages^[59]. M1 macrophages secrete pro-inflammatory cytokines such as TNF-α, IL-12, and IFN-β, which enhance antigen presentation and promote T-cell activation.

In recent years, the role of neutrophils in ultrasound-mediated immunotherapy has gradually garnered attention [Figure 3]. Tumor-associated neutrophils also exhibit two functional states: N1 and N2^[84]. The ultrasound-induced inflammatory microenvironment can promote the conversion of N2-type neutrophils to N1-type neutrophils^[85]. N1-type neutrophils can release ROS, TNF-α, and chemokines, and promote the recruitment of CD8⁺ T cells, thereby enhancing the antitumor immune response^[86,87].

In addition, natural killer (NK) cells are also involved in the early immune response induced by ultrasound. Increased expression of stress ligands on the surface of damaged tumor cells promotes NK cell activation and enhances their ability to release perforin and granzyme, thereby further eliminating tumor cells^[88,89].

The adaptive immune response is a key factor determining the long-term efficacy of ultrasound-mediated immunotherapy. Mature dendritic cells present captured tumor antigens to naive T cells, thereby initiating an antigen-specific immune response.

CD8⁺ cytotoxic T lymphocytes are the primary effector cells of antitumor immunity. Under MHC-I molecule-mediated antigen presentation, CD8⁺ T cells undergo clonal expansion and migrate to tumor tissue, where they directly kill tumor cells by releasing perforin and granzyme^[90,91]. Numerous studies have confirmed that one of the key indicators of successful ultrasound immunotherapy is a significant increase in CD8⁺ T-cell infiltration within tumor tissue. CD4⁺ helper T cells support the expansion and functional maintenance of CD8⁺ T cells by secreting cytokines such as IL-2, IFN-γ, and TNF-α, while also coordinating the joint participation of B cells and innate immune cells in the antitumor response^[92-94].

Notably, the massive release of tumor antigens induced by ultrasound can also increase T-cell receptor (TCR) repertoire diversity, enabling the body to recognize more tumor neoantigens and thereby reducing the risk of tumor immune evasion^[95]. Furthermore, some effector T cells can further differentiate into memory T cells, including central memory T cells and effector memory T cells^[96,97]. These cells persist in the body for extended periods and can rapidly mount an immune response upon tumor recurrence, ensuring long-term antitumor immune surveillance.

The most compelling feature of ultrasound immunotherapy lies in its ability to transform localized treatment into a systemic antitumor immune response. Although the ultrasound effect is confined to the local lesion, the immune response it induces can spread throughout the body via the circulatory system.

The abscopal effect is a classic manifestation of systemic immune activation. Following ultrasound treatment of the primary tumor, large numbers of activated tumor-specific T cells enter the circulatory system and migrate to distant metastatic sites, thereby inhibiting the growth of tumors that have not been directly treated^[98]. A growing body of research indicates that combining ultrasound with immune checkpoint blockade therapy can significantly enhance the abscopal effect and improve control of metastatic tumors.

Systemic immune activation can also effectively eliminate circulating tumor cells (CTCs) and micrometastases, thereby reducing the risk of tumor metastasis. At the same time, the formation of memory T cells endows the body with long-term immune surveillance capabilities, enabling it to rapidly mount an immune response upon tumor recurrence and prevent tumor regrowth^[99-101].

Therefore, the ultimate goal of ultrasound-mediated immunotherapy is no longer limited to localized tumor ablation but rather involves transitioning from localized treatment to systemic antitumor immunity by inducing ICD, activating innate and adaptive immunity, and establishing immune memory. This process constitutes a complete biological chain of logic “from immunogenic cell death to systemic immune activation” and provides an important theoretical foundation for the design of future ultrasound-mediated immunotherapy strategies empowered by nanomedicine.

Ultrasound-induced SDT can lead to massive tumor cell death, accompanied by ICD hallmarks such as CRT exposure, ATP release, and HMGB1 secretion. When tumor-associated antigens and DAMPs are taken up by dendritic cells, they promote dendritic cell maturation and enhance their ability to cross-present antigens, ultimately inducing the expansion of tumor-specific CD8⁺ T cells. However, once activated T cells enter tumor tissue, they are often suppressed by immune checkpoint signaling, such as PD-1/PD-L1 and CTLA-4.

PD-1 is a negative regulatory receptor expressed on the surface of activated T cells. Upon binding to PD-L1 on the surface of tumor cells, it inhibits TCR signaling, reduces the release of cytotoxic molecules (granzyme B and perforin), and induces T-cell exhaustion. At the same time, the ultrasound-induced inflammatory response and IFN-γ release may, conversely, further promote PD-L1 expression, leading to adaptive immune tolerance.

The sound-activated semiconductor polymer nano-feedback system (SPN_SA) developed by Yu et al. takes advantage of this mechanism: Upon ultrasonic activation, the H₂O₂ generated by SPNs not only mediates ICD induced by sonodynamic therapy but also cleaves the linker to release the loaded aPD-L1, precisely blocking the upregulated PD-L1 pathway^[115]. This acts synergistically with antigen release induced by SDT, achieving simultaneous suppression of primary and distant tumors in a bilateral 4T1 tumor model^[115]. In addition to PD-L1, the adenosine/A2AR pathway is also a key immunosuppressive feedback mechanism following ICD. By using SPN_SA to simultaneously release the A2AR antagonist SCH58261, the research team achieved dual-pathway blockade, which further amplified the antitumor immune response [Figure 4].

CTLA-4 primarily acts during the T-cell activation phase by competitively binding to CD80/CD86 molecules on the surface of dendritic cells, thereby inhibiting the formation of co-stimulatory signals and limiting initial T-cell activation. The massive release of tumor antigens induced by ultrasound provides the foundation for T-cell activation, while CTLA-4 blockade further enhances T-cell clonal expansion^[116]. In the future, therapeutic strategies combining ultrasound immunotherapy with CTLA-4 blockade are expected to be developed. By enhancing T-cell priming and clonal expansion, these strategies can effectively reverse the tumor-suppressive immune microenvironment, thereby further enhancing the level of antitumor immune response^[117]. The combination of these two approaches not only enhances local tumor killing but also promotes the formation of memory T cells, thereby establishing long-term immune surveillance.

The cGAS-STING pathway is a key signaling axis through which the body recognizes cytoplasmic DNA and initiates innate immune responses, playing a central role in linking innate and adaptive immunity. Ultrasound-induced ROS-mediated damage and cell death can lead to the release of nuclear and mitochondrial DNA from tumor cells into the cytoplasm^[118]. Upon recognition of cytoplasmic DNA by cyclic GMP-AMP synthase (cGAS), cGAS catalyzes the production of the second messenger cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), which subsequently activates the STING protein on the endoplasmic reticulum. Activated STING recruits TANK-binding kinase 1 (TBK1) and promotes the phosphorylation of IRF3, thereby inducing the production of large amounts of type I interferons (IFN-α/β). Type I interferons not only promote dendritic cell maturation but also enhance their ability to cross-present antigens and induce the expression of chemokines such as CXCL9 and CXCL10, thereby facilitating the recruitment of CD8⁺ T cells to tumor tissues. Consequently, the STING pathway is considered a key switch for initiating the immune response in “cold tumors”.

However, because some tumor cells exhibit STING signaling defects or insufficient accumulation of cytoplasmic DNA, relying solely on ultrasound-induced endogenous DNA release often fails to fully activate the cGAS-STING pathway. To address this issue, Lei et al. developed a mitochondria-targeted sonodynamic nanoplatform, TPP@CoTCPP, which enhances ultrasound-induced ROS production through TPP-mediated mitochondrial targeting^[119]. Abundant ROS induce mitochondrial damage and mitochondrial permeability transition pore (mPTP) opening, promoting the release of mtDNA into the cytoplasm and thereby activating the cGAS-STING-TBK1-IRF3 signaling axis [Figure 5]. Further studies have shown that this strategy not only significantly enhances the expression of STING-related signaling molecules but also promotes the transition of macrophages to a pro-inflammatory phenotype. Together with sonodynamic therapy-induced immunogenic cell death, it amplifies the antitumor immune response, providing a new design approach for utilizing ultrasound to activate the innate immune system.

Ferroptosis is a form of programmed cell death driven by iron-dependent lipid peroxidation, and its progression exhibits a high degree of synergy with ultrasound-induced ROS production. The large amount of ROS generated during SDT continuously attacks the polyunsaturated fatty acids in the cell membrane, leading to the continuous accumulation of lipid peroxides. When GPX4 activity is inhibited, cells are unable to clear lipid peroxides in a timely manner, ultimately inducing ferroptosis^[120]. At the same time, iron ions continuously generate hydroxyl radicals via the Fenton reaction, further amplifying oxidative damage.

Compared with conventional apoptosis, ferroptosis exhibits greater immunogenicity; ferroptotic cells release signaling molecules such as oxidized phospholipids, HMGB1, and ATP, thereby promoting dendritic cell maturation and antigen uptake. Furthermore, activated CD8⁺ T cells release IFN-γ, which downregulates solute carrier family 7 member 11 (SLC7A11) expression in tumor cells, further enhancing sensitivity to ferroptosis^[121]. The continuous inertial cavitation strategy developed by Yin et al. induces the generation of large amounts of ROS via ultrasound, which synergizes with ferroptosis inducers to significantly enhance lipid peroxidation levels and ICD effects, thereby achieving highly effective tumor suppression and immune activation in a breast cancer model^[122]. Similarly, the dual-programmed sonodynamic-ferroptosis nano-PROTAC platform (SPNFeP) developed by Wang et al. utilizes the synergistic amplification of oxidative stress through ultrasound-triggered singlet oxygen generation and hydroxyl radicals produced by the Fenton reaction^[123]. This significantly promotes lipid peroxidation and GPX4 downregulation, inducing intense ferroptosis and ICD responses, as evidenced by increased CRT exposure, ATP release, and HMGB1 secretion; This further enhances dendritic cell maturation and CD8⁺ T-cell infiltration while reducing MDSC accumulation, thereby achieving effective immune activation and complete suppression of deep-seated tumors [Figure 6].

In addition to immune checkpoint inhibitors and STING activators, ultrasound-mediated immunotherapy can also work synergistically with emerging immunotherapeutic strategies such as adoptive cell therapy (ACT) and tumor vaccines. ACT includes cell therapies such as CAR-T and CAR-NK^[124], whose efficacy in solid tumors is often limited by the immunosuppressive tumor microenvironment and physical barriers^[125]. Ultrasound-induced ICD can release large amounts of tumor antigens and inflammatory signals, promoting dendritic cell maturation, enhancing the recruitment of effector T cells, and improving the local immune status of the tumor, thereby creating favorable conditions for ACT cell infiltration and functional exertion. At the same time, some ultrasound-responsive nanoplatforms can further enhance the antitumor activity of cell therapy by regulating tumor metabolism, alleviating hypoxia, and lifting immune suppression. To address these bottlenecks, recent research has developed a chemokine-based injectable navigation system (CITE). This system achieves sustained release by forming a drug reservoir through the peritumoral injection of a thermosensitive immunogel co-loaded with CXCL9-conjugated particles and the PD-1 antibody (aPD1). Simultaneously, intravenous injection of the tumor-penetrating peptide iRGD promotes the accumulation of the gel-released drug within the tumor. On the one hand, this creates a sustained CXCL9 chemotactic gradient at the tumor site, guiding CXCR3-expressing CAR-T/TCR-T cells to migrate specifically to the tumor, thereby maximizing the number of migrated T cells within the tumor. On the other hand, aPD-1 blocks immune suppression pathways to enhance the functional activity of infiltrating T cells [Figure 7].

Furthermore, ultrasound immunotherapy and tumor vaccines exhibit natural synergy. Ultrasound-induced tumor cell death releases abundant tumor-associated antigens (TAAs), neoantigens, and DAMPs such as CRT, ATP, and HMGB1, creating an effect similar to an “in situ vaccine” that significantly enhances antigen presentation efficiency and T-cell activation capacity^[127]. In recent years, various ultrasound-responsive nanoplatforms have been used in combination with personalized tumor vaccines or messenger RNA (mRNA) vaccines to achieve a stronger systemic antitumor immune response by simultaneously enhancing antigen release, cross-presentation, and the formation of immune memory.

In summary, although the target molecules and mechanisms of action vary among different combination therapy strategies, they all essentially promote the transition from local immune activation to systemic antitumor immunity by synergistically regulating multiple key components of the Cancer-Immunity Cycle [Figure 8].