## 3 Nanostructured Systems for Cancer Immunotherapy
[PERSON] and colleagues [99] have also assessed the benefits of cyclodextrins as valuable nanocarriers for the dual delivery of NLG919 (i.e., a nontoxic IDO1-selective inhibitor that blocks IDO-mediated immune suppressive pathways) and paclitaxel. The proposed formulation enhanced the solubility of carried agents, significantly enhancing its anti-tumor activity. Alternatively, [PERSON] et al. [100] created a bone marrow mesenchymal stem cell (BM-MSC) exosome-based biosystem to deliver galectin-9 siRNA and oxaliplatin. This delivery approach resulted in augmented drug accumulation in the tumor site, efficient tumor-suppressive macrophage polarization, cytotoxic T lymphocyte recruitment, and T regulatory cells (Tregs) downregulation. Several interesting studies have exploited the excellent biocompatibility of DNA nanostructures [40] to create tetrahedron-shaped nanocarriers of interest in chemoimmunotherapy. For instance, [PERSON] et al. [101] introduced a tetrahedral framework nucleic acid immune adjuvant (FNAIA) designed to penetrate the skin and deliver doxorubicin and CpG oligodeoxynucleotides directly into melanoma tumors. The proposed strategy allowed for deeper tumor penetration, enhanced dendritic cell activation compared to free CpG, immunogenic cell death induction, effective tumor growth inhibition, and increased CD8\({}^{+}\) T cell infiltration. [PERSON] et al. [40] similarly employed DNA tetrahedrons to deliver doxorubicin, combining this chemotherapeutic load with the immunotherapeutic agent CpG oligodeoxynucleotides. The researchers also obtained synergistic therapeutic outcomes, indicating the promise of the developed system for treating cancer. Similarly, [PERSON] et al. [102] reported on the fabrication of self-assembled tetrahedral framework nucleic acid (tFNA) nanocarriers able to transport doxorubicin and CpG. This combination produced a strong antitumor immune response, including CD8\({}^{+}\) T cell proliferation and antitumor cytokine TNF-\(\alpha\) and IFN-\(\gamma\) secretion. Moreover, when combined with PD-L1 inhibitors, it further boosted therapeutic efficacy, offering a promising strategy for clinical cancer treatment. Besides the combination with chemotherapy, immunotherapy can also be applied in association with radiotherapy, a strategy currently used in treating lymphoma patients. Radioimmunotherapy employs complexes made of a targeting molecule (often an antibody), radionuclide chelates, and a linker. The linker may assume a nanoparticulate form, especially as nanoparticles allow multiple radionuclides and targeting groups in one complex [103; 104; 105]. With these aspects in mind, [PERSON] et al. [103] explored Cetuximab-targeted [177 Lu]-AuNPs for their ability to bind EGFR and inhibit tumor growth in Cetuximab-resistant colorectal cancer cells, showing high affinity and potential as an effective treatment to improve radioimmunotherapy results. Despite the extensive research in nanotechnology and its potential to revolutionize cancer immunotherapy, a significant gap remains between preclinical research and clinical application. While numerous studies on nanostructured carriers have demonstratedpromising outcomes regarding safety, biological performance, and enhanced therapeutic efficacy, most have not reached the clinical testing phase. Many nano-formulations are still in the early stages of safety and biological performance evaluations. As of August 2024, only two clinical studies on the ClinicalTrials.gov platform related to immunotherapeutic delivery systems for malignant diseases had been registered. Both studies, however, reported \"unknown status\" and had not yet posted any results, highlighting the challenges in translating experimental approaches into clinical practice. Table 1 summarizes these registered clinical trials, including details on study design, intervention types, and expected completion dates. This snapshot illustrates the current limitations in clinical progress despite the extensive research efforts focused on nanomedicine in cancer immunotherapy.