4.1 MOFs for regulating the TME

In the field of tumor therapy, MOFs have exhibited tremendous potential in modulating the TME due to their unique structures and tunability. Through meticulous design and functionalization, MOFs can intervene in critical factors within the TME, thereby improving its immunosuppressive state and enhancing the efficacy of immunotherapy. Specifically, MOFs can regulate the TME in various ways. On one hand, they can augment the oxygen supply to tumor tissues, thereby alleviating hypoxia-induced immunosuppression. For instance, a reported study introduced a biomimetic self-supplying oxygen nanocatalytic drug, O₂@UiO-66@ICG@RBC, which employs the porous structure of MOFs to load oxygen-generating agents, achieving sustained oxygen supply within tumors.⁴⁸ This strategy provides a direction for improving hypoxic tumor therapy and facilitates the sensitivity of tumor cells to immunotherapy.

On the other hand, MOFs can deplete glutathione (GSH) within tumor tissues, thereby disrupting their redox balance. GSH is a crucial antioxidant found in high concentrations within the TME, capable of neutralizing reactive oxygen species (ROS) and reducing the efficacy of immunotherapy. In the study conducted by Ma et al., a bimetallic Zn²⁺/Cu²⁺ co-doped MOF was reported to deplete GSH and generate ROS, thereby dismantling the antioxidant defense mechanism of tumor cells and creating favorable conditions for immunotherapy.⁴⁹

Furthermore, MOFs can act as catalysts to continuously enhance the TME through sustained catalytic reactions. The MnFe₂O₄@MOF nanoplatfrom designed by researchers exemplifies this approach. This material can catalyze the conversion of H₂O₂ to O₂ by a Fenton-like reaction in an acidic TME.⁵⁰ This catalytic reaction not only mitigates the hypoxic state of tumors but also produces a significant amount of ROS, directly damaging tumor cells and thereby augmenting the antitumor efficacy of PDT. In summary, by modulating the TME through mechanisms such as enhancing oxygen supply, depleting GSH, and sustaining catalytic reactions, MOFs can significantly improve the effectiveness of immunotherapy.

Tumor-infiltrating lymphocytes (TILs) often face resistance, while the presence of immunosuppressive cells, particularly myeloid-derived suppressor cells (MDSCs), poses significant challenges in combating “cold“ tumors.^51-53 To overcome this challenge, Chen et al.⁵⁴ and colleagues devised a method involving the utilization of cationic dendrimer molecules (PDGs) loaded with guicasibine, which were then bound to PCN-224 through electrostatic adsorption. The combination of GEM with PDT facilitated the infiltration of cytotoxic T lymphocytes (CTLs) into the tumor, aiding in the remodeling of the TME.

4.2 MOFs for improved ICB therapy

PD-1 is a crucial immunosuppressive molecule found in high levels on the surface of activated T cells.⁵⁵ Its primary function is to shield normal tissues from immune attack by engaging with PD-L1, thereby obstructing T cell receptors and suppressing costimulatory signaling. When tumor cells express PD-L1, they can bind to PD-1 on T cells, hindering their activation and proliferation.⁵⁶ This interaction facilitates immune evasion by tumors. In recent years, ICIs have become more widely used in clinical practice.⁵⁷ ZIFs offer several advantages, including high porosity, stability, and tunable surface properties, making them promising candidates for targeted drug delivery.⁵⁸ Recent studies have demonstrated the efficacy of MOFs in delivering ICIs.^28-31

In a study by Alsaiari et al.,²⁸ the delivery of nivolumab (NV), a PD-1 inhibitor, was achieved using biomimetic ZIFs. By encapsulating NV in NV-ZIF, the researchers achieved controlled release kinetics, improving the drug's efficacy in treating hematologic malignancies. Additionally, the surface modification of ZIF-8 with cancer cell membranes demonstrates a novel approach to targeted delivery, which could significantly impact the treatment of solid tumors. Ge et al.²⁹ utilized ZIF-8 as a carrier loaded with curcumin and the PD-L1 inhibitor BMS-1166 to augment the immunotherapeutic response of PD-1/PD-L1 blockade by inducing immunogenic cell death (ICD) through autophagic cell death. This highlights ZIF-8's potential in enhancing PD-1/PD-L1 blockade therapies.

Jiang et al.³⁰ pioneered the synthesis of MOF nanocrystals with distinct two-dimensional morphology, employing the rare-earth element dysprosium (Dy) coordinated with Tetrakis(4-carboxyphenyl) porphyrin (TCPP) as shown in Figure 2A, demonstrated promising results in downregulating PD-L1 expression in tumor cells. Bai et al.³¹ developed tumor cell membrane-encapsulated PCN-224 for targeted delivery of photosensitizers and small interfering RNAs (siRNAs) to knock down cyclin-dependent kinase 4 (Cdk4) (Figure 2B). The study highlighted a novel strategy for targeted delivery of therapeutic agents to inhibit Cdk4, thereby modulating PD-L1 expression and enhancing antitumor immune responses. IDO-1 inhibitors are another class of ICIs.⁵⁹ Indoleamine 2,3-dioxygenase (IDO-1) serves as an endogenous immunosuppressive mediator, promoting the accumulation of regulatory T cells (Treg) and dampening T cell activity through tryptophan (Trp) depletion within the microenvironment.^60-62 By blocking IDO-1 activity, IDO-1 inhibitors enhance the immune system's ability to attack tumor cells.⁶³ Zhang et al.³² using MOFs like ZIF-8 for dual delivery of chemotherapeutics and siRNA to target ICD and counteract Treg-mediated immunosuppression, enhancing localized drug concentration and reducing systemic toxicity (Figure 2C,D). This dual delivery system not only promises increased localized drug concentration but also precise targeting, thereby reducing systemic toxicity. Similarly, Du et al.'s³³ development of a GSH-sensitive MOF for delivering an IDO-1 inhibitor and an NO donor underscores the capability of responsive nanocarriers to leverage the TME for therapeutic gain. The rapid disintegration of these carriers in response to GSH levels ensures timely release of therapeutic agents, which is crucial for maximizing the pharmacological response while minimizing side effects. Furthermore, Fan et al.³⁴ used ZIF-8 for delivering both a chemotherapeutic and IDO-1 inhibitor in osteosarcoma, showcasing the adaptability of nanocarriers across different cancers. These strategies enhance and personalize cancer treatments.

In the field of cancer research, employing nanotechnology for drug delivery systems significantly enhances the efficacy of immunotherapy treatments.^{64, 65} The integration of nanotechnology in cancer treatment through the development of hybrid nanomedicines exemplifies a significant advancement in targeted cancer therapy.⁶⁶ The integration of MOF and nanotechnology enables the precise targeted delivery and the controlled release of ICI. By employing UiO-66 as a scaffold, Ding et al.³⁵ utilized UiO-66 to create functionalized AuMOF nanoparticles for controlled loading and release of the IDO inhibitor NLG929. Through π-π stacking and gold-thiol interactions, the nanoparticles ensured drug stability and effective release in response to specific triggers like light and the tumor biochemical environment. This approach addresses challenges in drug delivery, such as nonspecific distribution and premature release.

4.3 MOFs for immunomodulator-based cancer immunotherapy

Studies have shown that MOFs exhibit great potential as multifunctional nanocarriers in tumor immunotherapy.^67-70 Firstly, as a multifunctional nanocarrier, MOF is highly tunable and controllable for efficient delivery and release of immunomodulators. pH-responsive nanocarriers have attracted much attention for their ability to respond to the acidic TME for controlled release.^{71, 72} ZIF-8 nanoparticles are widely utilized as carriers for tumor therapy due to their high porosity, adjustable pore size, ease of preparation, and pH responsiveness.³⁶ However, the inherent therapeutic efficacy and immunogenicity of ZIF-8 remain uncertain. Initial observations by Ding et al.^{35, 36} found that ZIF-8 NPs cause tumor cell death through necrosis and ICD by releasing inflammatory molecules and DAMPs, enhancing immunogenicity and initiating an immune response. In a related study, Zhao et al.³⁸ used pH-sensitive ZIF-8 NPs loaded with perforin and granzyme B, targeting CD8⁺ T cells, which showed enhanced cytolytic activity in acidic lysosomal environments. Adding elements like calcium carbonate ensures immunostimulatory agents are released where needed, boosting CTL activation and effectiveness.

Secondly, the structural features of MOF allow it to achieve targeted delivery through various modifications, such as chemical modification and biological modification, thus increasing the enrichment of immunomodulators at the tumor site and reducing the damage to healthy tissues. Zhang et al.³⁷ advanced the use of ZIF-8 in targeted nanoparticle therapies for immunotherapy. By customizing nanoparticles with ligands like hyaluronic acid (HA) and mannose, they target tumor and immune cell markers, enhancing therapeutic delivery and addressing immune evasion in tumors.^73-75 In a separate study, Yang et al.⁴⁴ encapsulated mammalian cells with ZIF-8 NPs using the AS1411 aptamer, inducing ICD in cancer cells. This process activates immune pathways, including tumor necrosis factor signaling, cytokine-cytokine receptor interaction, and toll-like receptor signaling. In particular, MOF carriers enable the induction of ICD via aptamers, thus enhancing the immunotherapeutic effect.⁷⁶ These findings suggest a potential adjuvant role for ZIF-8 NP coating in tumor therapy.

Interestingly, MOF may also have a role as an immune adjuvant. Through its unique composition and recognition properties, MOF not only serves as a carrier for therapeutic agents but also actively engages with the immune system, driving antitumor responses. Dai⁴³ and colleagues designed a MOF containing Gd³⁺ and Zn²⁺ as metal nodes, with 1,4-benzyl dicarboxylic acid as the organic ligand. Their aim was to investigate the MOF's impact on cellular signaling in the immune response. They found that intracellular Gd³⁺ competes with Ca²⁺ for binding to TMEM 16 F, which results in the inhibition of phosphatidylserine (PS) externalization by suppressing TMEM 16 F activity. This process is depicted in Figure 3A–D. Zn²⁺ acts as an immunomodulator, suppressing immunosuppressive PS signaling, and simultaneously serves as an ICD inducer, enhancing immunostimulatory signaling. Hepatocellular carcinoma (HCC) is a common primary cancer characterized by high morbidity and mortality.⁷⁷ Chen et al.⁴² engineered MOF-801 via the combination of Zr6 clusters and fumaric acid. Acting as a conveyance mechanism, MOF-801 demonstrates the ability to trigger the cGAS-STING-NF-κB signaling cascade by recognizing toll-like receptor 4 (TLR4) at remarkably low concentrations (70 ng/mL). This activation expedites the maturation of DCs. CpG ODNs and the STING agonist DMXAA were incorporated into MOF-801 to counter immunosuppression and provoke potent antitumor immunity in HCC settings (refer to Figure 3E). Theirs study underscores the multifaceted capabilities of MOF-801 in cancer immunotherapy.

The combination of precise tumor targeting, controlled release of immune adjuvants and synergistic photoimmunotherapy significantly improves tumor cytotoxicity, ultimately leading to high cure rates and minimal systemic side effects. The strategic manipulation of tumor-associated macrophages (TAMs) highlights a sophisticated approach in the treatment of cancer.^{78, 79} TAMs, which infiltrate tumors, exhibit dual behaviors that significantly influence cancer therapy outcomes.⁸⁰ M1-like TAMs are beneficial for their tumor-destroying capabilities and ability to trigger Th1-type immune responses, while M2-like TAMs promote tumor growth, angiogenesis, metastasis, and suppress T cell-mediated antitumor immunity.^{81, 82} Wei et al.‘s⁴⁰ developed iron-based MOFs targeting M2-like TAMs using an M2pep-modified system to reprogram M2 macrophages into M1 macrophages. This strategy boosts the immune system's ability to fight cancer and reduces recurrence risks. Ni et al.⁴¹ used Hf-DBP nanoparticles to co-deliver IMD and αCD47, regulating macrophage function and countering tumor-induced immune suppression. This multi-target approach integrates immunomodulatory and phagocytosis-promoting agents, transforming the TME into a more immunostimulatory state. In summary, as a carrier of immunomodulators, MOF has good biocompatibility, targeting and controllability, and is expected to become an effective tool for tumor immunotherapy.

4.4 MOFs for enhanced cancer vaccine strategies

Vaccination, widely recognized as a secure and efficacious preventive measure against various infections.⁸³ However, developing vaccines for cancer remains an immense challenge. MOFs have emerged as an effective tool to enhance cancer immunotherapy through efficient antigen delivery, immune stimulation and induction of ICD. MOFs facilitate the efficient loading and delivery of antigens, such as ovalbumin (OVA), to target cells.⁸⁴ Zhong et al.⁴⁵ initiated a synthesis of nanoparticles (termed ZANPs), integrating aluminum, the model antigen OVA, and ZIF-8. They achieved a loading efficiency of 30.6% using ZANPs, demonstrating the effectiveness of MOFs in antigen delivery.

MOFs can enhance antigen immunostimulatory properties by facilitating intracellular antigen release, promoting cross-presentation, and immune activation. Ni et al.‘s development of hafnium-based MOFs for targeted cancer therapy is a significant breakthrough in immunotherapy.⁴⁶ These MOFs bind and deliver CpG oligodeoxynucleotides, activating the immune system directly within theTME. Exposure to X-rays enables MOFs to generate ROS, releasing tumor antigens and DAMPs, which enhance antigen-presenting cell maturation and boost CTL populations in tumor-draining lymph nodes. Combined with ICIs, this strategy significantly enhances innate and adaptive immune responses, leading to notable tumor regression and sustained immune memory, highlighting MOFs’ potential in in situ cancer vaccines.

Nanocarriers based on MOFs can also promote the recruitment of antigen-presenting cells.⁸⁵ MOFs can attract DCs into the TME enhancing T cell-mediated immune responses, which are crucial for inhibiting tumor metastasis. Yalamandala et al.⁴⁷ introduced a novel in situ catalytic nanoserver (CN), comprising a PNIPAAM/PDA hybrid nanogel, catechol-functionalized MOFs, and MnO₂, targeting lung metastasis and enhancing immune responses (Figure 4). This MOF-based nanocarrier catalyzes redox reactions to generate Mn²⁺, induces apoptosis and releases antigens within tumor metastases. Catechol-functionalized MOFs capture released antigens, forming a reservoir that promotes prolonged immune activation. This process not only triggers ICD but also attracts DCs, enhancing T-cell mediated immune responses and promote prolonged immune activation. These findings collectively stress the potential of MOFs in developing in-situ cancer vaccines, offering promising avenues for enhancing cancer immunotherapy. MOFs serve as multifunctional platforms for cancer immunotherapy through efficient antigen delivery and immune stimulation, promoting immune responses and tumor regression. Further research into MOF-based strategies holds promise for developing more effective in-situ cancer vaccines, further enhancing immune responses, and promoting tumor regression.

4.5 MOFs for immunogenicity-augmented cancer immunotherapy

ICD is a distinct type of apoptosis that allows immune-capable hosts to initiate specific immune responses against antigens from dead cells.^{86, 87} Surface-exposed calreticulin (CRT) sends “eat me” signals to DCs; released high-mobility group box 1 (HMGB1) enhances DC maturation and antigen presentation to CTLs; and secreted ATP drives CTL infiltration into tumors.⁵⁴ This process counteracts the tumor's immunosuppressive environment and enhances the effectiveness of immunotherapy. MOFs-based drug delivery systems trigger ICD by integrating chemotherapeutic drugs, photosensitizers, radiosensitizers, and immunomodulators.^88-90 These systems specifically target and release drugs at the tumor site, improving biosafety and therapeutic outcomes.^{91, 92} This section will overview the role of MOFs in inducing ICD for tumor treatment.

4.5.1 Chemotherapy-driven immunogenic activation

Chemotherapy remains one of the most effective strategies for treating cancer.^{93, 94} Recently, the emergence of chemoimmunotherapy, which combines chemotherapy and immunotherapy, has shown promising synergistic effects in cancer treatment. Chemotherapeutic agents such as paclitaxel, oxaliplatin (Oxa), and doxorubicin (DOX) not only directly kill cancer cells but also activate both innate and adaptive immune responses, thereby inducing ICD.^{95, 96} To enhance the effects of chemotherapy-induced ICD, Wang et al.⁹⁷ introduced a novel biomimetic nanosystem utilizing ZIF-8 nanoparticles to enhance chemotherapy-induced ICD and modulate the immunosuppressive TME (iTME), as shown in Figure 5A–C. Biomimetic materials often have the ability to be self-adaptive and self-healing.⁹⁹ By integrating ZIF-8 nanoparticles that release lactate oxidase (Lox) and Oxa, this system targets the metabolic and immunologic dysregulation within tumors. Within this system, Lox is released to convert lactate, thereby shifting the acidic tumor environment, promoting the polarization of macrophages from M2 to M1, and reducing Tregs. The release of Oxa further induces ICD, facilitating the clearance of cancer cells by CTLs and M1 macrophages. Hu et al.¹⁰⁰ formulated PCN-Oxpt/PEG, a multifunctional, biocompatible nanotherapeutic that targets the TME to enhance the efficacy of cancer treatments through chemotherapy, ferroptosis, and immunomodulation. This system uses a chemically modified form of oxaliplatin, Oxpt (IV)-COOH, to deplete GSH in tumor cells, facilitating the generation of hydrogen peroxide and subsequent production of cytotoxic hydroxyl radicals via ferroptosis, thereby promoting ICD. Enhanced by dual-mode imaging capabilities, this approach optimizes drug delivery and effectiveness.

4.5.3 PDT-driven immunogenic activation

PDT utilizes three inherently safe components: a photosensitizer, light, and oxygen in the target tissue. This combination produces ROS, predominantly singlet oxygen (¹O₂), which initiate cell death through apoptosis and necrosis.^{108, 109} PDT also has a strong immunogenic effect and can induce ICD.^{110, 111} For the photodynamic effect, MOFs frequently incorporate porphyrins as organic ligands to create porous nanocarriers.

MOFs are modified to significantly increase NIR absorption, which can more effectively initiate PDT in deeper tissues.^{112, 113} In an innovative research, Li et al.¹¹⁴ synthesized PCN-222 nanoparticles using a solvothermal technique with TCPP as a ligand, Zr⁴⁺ as the metal center, and dichloroacetic acid as a modifier. These NPs were then transformed into spindle-shaped PCN-SUs with enhanced NIR absorption through a sulfonation reaction. This modification, introducing sulfonic acid anions to the TCPP ligand, led to porphyrin ring distortions that effectively narrowed the energy gap between the HOMO and LOMO, thereby significantly enhancing NIR absorption. The resulting PCN-SU nanoparticles exhibited superior photoactive properties, notably in generating singlet oxygen under NIR light, effectively inducing ICD, and promoting DC maturation more efficiently than their PCN-222 counterparts. This development shows the potential of PCN-SU as a powerful tool in cancer immunotherapy. Wang et al.¹¹⁵ successfully developed PCN-224 nanoparticles using a solvothermal method with TCPP as a ligand, Zr⁴⁺ as the metal core, and DMF as the modifier. They incorporated BSO into the nanoparticles, which was targeted to tumor sites with HA. BSO inhibits GSH synthesis and GPX activity while increasing ROS, inducing ferroptosis and effectively combining with PDT to promote ICD in tumor cells. Simultaneously, Cai et al.¹¹⁶ enhanced this design by adding ACF and CpG within an HA coating to inhibit hypoxia-inducible factor 1-alpha (HIF-1α).

Some MOFs are capable of altering the TME and alleviating hypoxia, a common challenge in solid tumors, thereby improving the efficacy of PDT.^{117, 118} Sun et al.¹¹⁹ engineered another variant of PCN-224, incorporating carbocyanide 3-chlorophenylhydrazine (CCCP), a compound that disrupts mitochondrial function, within a manganese dioxide (MnO₂) shell. This innovative shell assists in the catalytic decomposition of hydrogen peroxide (H₂O₂) within the tumor environment, thereby alleviating hypoxia. CCCP intensifies mitochondrial dysfunction leading to enhanced autophagy. This, in turn, facilitates the release of tumor antigens, boosting the immune system's recognition and destruction of tumor cells, thus promoting autophagy-driven cell death and enhancing the overall immunogenic response. In addition to the commonly used Zr⁴⁺, other metal ions such as Al³⁺, Fe³⁺, and Mn³⁺ can also coordinate with porphyrins to create MOFs with varied functionalities. Chen et al.¹²⁰ developed a new nanomaterial, PCN(Al), using a solvent-thermal method with Al³⁺ and TCPP, subsequently enhancing it by depositing Cu (II) and Pt nanoparticles on its surface and modifying it with NH₂-PEG-FA (Figure 6A). This configuration allowed Cu (II) to target and reduce intracellular GSH, elevating ROS levels, while Pt nanoparticles converted H₂O₂ to O₂, reducing hypoxia and enhancing PDT's effectiveness in triggering ICD and a systemic immune response (Figure 6B–L). Concurrently, Li et al.¹²¹ synthesized PCN(Fe), using a similar approach with Fe³⁺ and TCPP, and enhanced it with Pt nanoparticles and a coating of RBCMs, improving circulation time and tumor targeting, thereby boosting PDT's antitumor efficacy.

MOFs offer a promising platform for synergistically integrating diverse therapeutic modalities, such as the combination of PDT and CDT, thereby expand the eradication of cancer cells.^122-124 The PDT capabilities of Pt nanoparticles are enhanced by their ability to generate ¹O₂. Additionally, in the presence of GSH, the iron in PCN(Fe) undergoes reduction from Fe³⁺ to Fe²⁺, promoting CDT. Both PDT and CDT work synergistically to intensify intracellular oxidative stress and amplify the ICD effect. Yu et al.¹²⁵ and Zhao et al.¹²⁶ have advanced nanoparticle-based therapies by integrating photodynamic and chemodynamic mechanisms to enhance tumor-targeted treatments. Yu et al. encapsulated tirapazamine (TPZ) in PCN(Fe) for simultaneous PDT and CDT applications, leveraging the dual mechanism to amplify intracellular oxidative stress and ICD. Zhao et al. developed PCN(Mn) nanoparticles, coordinated with Mn³⁺ and TCPP, for the delivery of vorinostat, modifying the nanoparticles with polyethyleneimine and AS1411 for targeted cancer therapy. These modifications facilitated the release of therapeutic agents within tumor cells, enhancing histone acetylation and activating the STING pathway, thereby boosting both innate and adaptive immune responses and significantly augmenting the therapeutic efficacy of PDT and CDT.

MOFs are fruitful in enhancing NIR absorption and PDT efficacy.^{127, 128} Xie et al.¹²⁹ and Lu et al.^{130, 131} conducted studies to enhance the efficiency of PDT through the synthesis of novel MOFs and porphyrin modifications. Xie et al. formulated PTP using a palladium-coordinated π-extended porphyrin (Pd-TBP), TCPP, and Zr⁴⁺, which exhibited dual NIR emission properties under a single excitation wavelength, useful for oxygen monitoring in tumor environments. Lu et al. modified porphyrin structures to chlorins, significantly boosting singlet oxygen production with the new DBC-UiO and TBC-Hf complexes, showing superior PDT efficacy compared to previous porphyrin-based frameworks.

Collectively, these investigations stress the potential of MOFs in cancer immunotherapy, showing their innovative modifications and applications in PDT-driven ICD. These advancements encompass the engineering of MOFs to enhance NIR absorption, modulate the TME, stimulate immune responses, and incorporate multiple therapeutic strategies. Each study contributes a distinct insight into the customization of MOFs to address the inherent limitations of conventional light-guided therapies, such as inadequate penetration depth, hypoxia, and insufficient tumor specificity. These findings illustrate a coherent progression from fundamental material synthesis and functionalization to sophisticated systems engineered for multimodal therapeutic and targeting mechanisms. Collectively, these initiatives have enhanced the efficacy, safety, and precision of PDT, advancing it towards clinical implementation in cancer treatment.

4.5.4 Radiodynamic therapy-driven immunogenic activation

Conventional visible light-activated MOFs used in PDT systems suffer from limited tissue penetration depth, typically less than 1 cm, which hampers their efficacy in treating deep-seated tissues. In contrast, RT employs deeply penetrating X-rays that directly damage DNA and indirectly generate hydroxyl radicals (-OH) to eradicate tumor cells, albeit with lower immunogenicity compared to PDT.¹³² Zhao et al.¹³³ introduced a novel approach for PDT by developing a MOF-based system that incorporates lanthanide-doped scintillant nanoparticles (SNPs) on the surface of PCN-224. This innovation aims to enhance deep-tissue radiodynamic therapy (RDT) and bolster antitumor immunity. Their method harnesses soft X-ray irradiation to activate a nanoprobe, facilitating energy transfer from SNPs to PCN-224 and significantly boosting ROS generation, particularly at depths of approximately 3 cm. Additionally, Li et al.¹³⁴ engineered ultrasmall MOF arrays, termed TZMs, utilizing tantalum (Ta) and zirconium (Zr) as metal nodes and TCPP as the photosensitizer (Figure 7A). These structures effectively attenuate X-ray energy, promoting hydroxyl radical production and facilitating energy transfer to enhance ¹O₂ generation, thereby augmenting the efficacy of RDT (Figure 7B–F).

Hafnium (Hf)-based MOFs have been documented to significantly augment the therapeutic effectiveness of ionizing radiation, such as X-rays, and serve as a potent adjunct therapy in synergy with cancer immunotherapy.¹³⁵ Within the Hf-periodic framework, heavy-element metal clusters efficiently absorb radiation, leading to the generation of -OH radicals. Concurrently, they transfer energy to neighboring photoconductors through inelastic scattering of photoelectrons in the radiation-excited hot spot region, facilitating the production of ¹O₂. As the X-ray absorption cross-section correlates positively with the atomic number of heavy metals, MOFs comprising heavy metals exhibit enhanced X-ray adsorption, thereby bolstering the radiotherapeutic effect. Ni et al.⁸⁸ have proposed the utilization of elemental bismuth (Bi), the heaviest naturally occurring nonradioactive element, for constructing MOFs as nano-sensitizers. The augmented kinetic effects of radiotherapy by Bi-MOFs induce stronger local immune activation.

4.5.5 Photothermal therapy (PTT)-driven immunogenic activation

PTT, which induces tumor cell death by generating high temperatures under near-infrared light irradiation, holds significant promise for cancer treatment.^{136, 137} PTT offers several advantages including high spatial selectivity and specificity, no resistance development, minimally invasive procedures, and minimal side effects.¹³⁸ By adding imaging agents and immunodrugs at the same time, MOFs can achieve both diagnostic and therapeutic functions. This dual function facilitates real-time monitoring of efficacy and targeted therapies, thereby improving overall treatment outcomes.¹⁸ The study by Zhang et al.¹³⁹ demonstrates the development of multifunctional nanoparticles termed DIMP NPs for potential therapeutic applications. These NPs were fabricated by incorporating ICG and DOX into ZIF-8 nanoparticles, followed by surface modification with polyvinylpyrrolidone (PVP). The inclusion of ICG within the NPs allows for various imaging modalities and therapeutic interventions, such as PTT and chemotherapy, while also enabling real-time monitoring of treatment efficacy.

Modified MOFs can be delivered to targeted tumor cells. This specificity reduces systemic side effects, increases the concentration of therapeutic drugs at the tumor site, and enhances the photothermal and chemotherapy effects. MIL-100, a material containing iron ions, can generate photothermal effects when irradiated with a 671-nm laser. Building on this property, Ni et al.¹⁴⁰ incorporated the anticancer drug mitoxantrone into MIL-100 and further modified it with HA to target tumors. Similarly, Liu et al.¹⁴¹ developed nanoparticles by co-loading ICG and Oxa into MIL-100, also utilizing HA for targeted delivery, as illustrated in Figure 8A. Moreover, when these nanoparticles are combined with a PD-L1 antibody, the resulting chemo-PTT not only targets tumors but also activates T-cells (Figure 8B–L). This activation enhances the efficacy of ICB, thereby promoting a systemic antitumor immune response.

By precisely controlling the release of immunomodulatory agents, MOFs can up-regulate immune response factors such as HSP70 to improve the efficacy of thermal immunotherapy.^{142, 143} Guo et al.¹⁴³ developed a novel approach for the programmed upregulation of immune response factors, enhancing the efficacy of thermal immunotherapy. They synthesized ZrMOF-NH₂ nanoparticles as carriers, encapsulating CSNO and GGA within nanoparticle channels, followed by sealing with l-menthol. Surface modification with triphenylphosphine yielded the GCZMT nano-amplifier. This nano-amplifier, administered intravenously, accumulates at tumor sites and responds well to microwave-induced heating. It mediates microwave thermotherapy, releasing NO, inducing mitochondrial damage, and promoting apoptosis. The combined effects of microwave heat, NO, and GGA systematically up-regulate HSP70 expression, fostering cytotoxic CD4⁺ and CD8⁺ T cell responses for effective antitumor immunotherapy. MOFs act as vectors to directly regulate the immune response, demonstrating an innovative approach to immunotherapy that programs the immune system to enhance antitumor activity by controlling agent release.

4.6 MOFs for imaging and diagnostic promotes immunotherapy

In the field of cancer therapy, the employment of MOFs for imaging and diagnostic purposes has significantly augmented the effectiveness of immunotherapy. Firstly, the integration of diagnosis and treatment enables a more precise localization of tumor characteristics, such as its location, size, and type. This enhanced specificity allows immunotherapy to target specific tumor cells, thereby augmenting therapeutic precision.^{33, 151} For instance, the HIFU-specific MOF nanosystem (ADMOFs) precisely guides HIFU surgery in MOF-guided imaging by targeting tumors and enhancing photoacoustic/magnetic resonance imaging effects, inhibiting tumor growth and eliminating lung metastasis, suggesting a promising strategy for enhancing cancer theranostics through combining hypoxia-activated chemo-immunotherapy with HIFU.¹⁵¹

Furthermore, the integrated diagnostic-therapeutic technique facilitates real-time guidance during the treatment process, ensuring that immunotherapeutic agents or cells are delivered accurately to the tumor site for optimal efficacy. Concurrently, it also enables the assessment of treatment outcomes, providing crucial insights for subsequent therapeutic planning.^{152, 153} In a study, Ma et al. developed a PD-L1-based electrochemical aptamer sensor that harnesses the synergistic effects of Fe3O4@UiO-66 nanocomposites and DNA nanocages.¹⁵² This innovation achieved real-time, high-sensitivity, and high-specificity guidance and prognostic evaluation for tumor immunotherapy. Concurrently, Feng et al. introduced EV-ANCHOR, a fluorescence aptamer sensor based on MOFs and cholesterol-triggered signal amplification, which enabled the efficient isolation and sensitive detection of PD-L1-positive extracellular vesicles in plasma.¹⁵³ This advancement significantly enhanced the efficacy of cancer diagnosis and the real-time assessment of immunotherapy.

Moreover, given the significant variations among cancer patients, standardized treatment protocols may not yield the optimal outcomes. The integrated diagnostic-therapeutic technology allows for the formulation of personalized immunotherapy regimens based on specific patient characteristics, such as disease severity, overall health status, and tumor type. This tailored approach ensures that immunotherapy is aligned with the patient's unique needs.^{155, 156} Fan et al.³⁹ explore the use of GSH-sensitive MIL101-amino MOFs in the ICG-CpG@MOF nanocarrier for targeted cancer therapy. This system delivers indocyanine green (ICG) and cytosine-phosphate-guanine (CpG) to tumors, leveraging the EPR effect for passive targeting and enabling advanced imaging (fluorescence, photoacoustic, photothermal, MRI). The GSH-responsive MOF releases immune adjuvants in the tumor environment, turning “cold” tumors “hot” by increasing immune activity. The study shows that ICG-CpG@MOF achieves tumor cell death and immune enhancement through photodynamic and PTT under 808-nm laser irradiation, leading to significant tumor cytotoxicity, high cure rates, and minimal side effects. Liu et al. construct Er³⁺-doped NaLnF4@MOF core@shell nanoparticles that integrate NIR-driven PDT and NIR-II imaging, enhancing the accuracy of therapy location tracking and significantly improving tumor inhibition when combined with α-PD-L1 immunotherapy.¹⁵⁴ In conclusion, the integration of diagnostic and therapeutic techniques in cancer therapy has ushered in more precise, efficient, and personalized immunotherapy strategies, ultimately contributing to improved patient outcomes and quality of life.