## 3 Nanostructured Systems for Cancer Immunotherapy
[64] developed a formulation based on plant virus cowpea mosaic virus (CPMV) conjugated with a multivalent display of anti-PD-1 peptides (SNTSEF) and proposed its utilization against metastatic ovarian cancer as an alternative to antibody therapies. On a different note, [PERSON] et al. [89] augmented immune checkpoint inhibition via antigen delivery by E2 nanoparticles comprising CpG oligonucleotide 1826 (CpG) and a glycoprotein 100 (gp100) melanoma antigen epitope (CpG-gp-E2). The formulation exhibited synergistic action against tumors, with durable antitumor responses suggesting the achievement of long-lasting immune memory. Differently, [PERSON] et al. [72] synthesized thermosensitive liposomes encapsulating resiquimod and combined them with \(\alpha\)PD-1, an immune checkpoint inhibitor, and ultrasound-mediated hyperthermia. The approach was demonstrated to be a viable option against the mouse mammary carcinoma model, producing tumor regression and prolonging survival. [PERSON] and colleagues [91] also combined anti-PD-1 therapy with nanostructured delivery systems. The researchers developed a bi-adjuvant neoantigen nanovaccine (banNV) for enhanced cancer immunotherapy. The banNV co-delivers a peptide neoantigen (Adpgk) with two adjuvants, TLR7/8 agonist R848 and TLR9 agonist CpG, sensitizing T cells to PD-1 and ensuring a complete regression of 70% of neoantigen-specific tumors. Alternatively, [PERSON] et al. [92] designed a library of biomimetic nanoparticles and identified phospholipid nanoparticles (PL1) as effective carriers for delivering CD137 or OX40 mRNA to T cells, proposing it in combination with anti-PD-1 and anti-CTLA-4 antibodies to boost cancer immunotherapy. Another interesting possibility was investigated by [PERSON] and colleagues [93], who explored the use of polydopamine nanoparticles (Pdop-NPs) grafted with a tumor antigen, ovalbumin (OVA), forming OVA@Pdop-NPs. The OVA@Pdop-NPs were found to be non-toxic and to even slightly enhance the viability of dendritic cells (BMDCs). They showed higher cellular uptake and better migration to lymph nodes compared to free OVA. Moreover, tests performed on mice with colon tumors revealed that the fabricated nanoparticles effectively activated cytotoxic T cells, produced memory T cells and significantly suppressed tumor growth, showing promise as potential vaccine vectors in cancer immunotherapy. Numerous recent studies have also focused on the possibility of enhancing therapeutic outcomes through a combined strategy of immunotherapy, chemotherapy, and nanomaterial-mediated delivery, especially given the potential of chemoimmunotherapy to restore drug efficacy. Smart nanoparticles have been designed for combinational therapy, delivering chemotherapeutic agents and nucleic acids either separately or simultaneously. Nonetheless, simultaneous delivery has been reported as more efficient, ensuring synchronized pharmacokinetics and precise dosing. Effective co-delivery requires ensuring that therapeutics reach tumors at desired concentrations, achieved by reducing drug leakage and employing stimuli-responsive, tumor-specific release mechanisms [28; 45; 94; 95; 96]. One example of such a synergistic system is offered by [PERSON] et al. [97]. The authors created a dual-responsive polyplex comprising methoxypoly(ethylene glycol)-polylacidide-polyhistidine-ss-oligoethylenimine (mPEG-\(b\)-PLA-PHis-ss0 OEI) and used it as a carrier for doxorubicin and MDR1 siRNA. The co-release of these therapeutic agents was triggered by pH/redox stimuli present in the TME, leading to enhanced _MDR1_ gene silence efficiency, cytotoxicity against MCF-7/ADR cells, and stronger MCF-7/ADR tumor growth inhibition. Another study by [PERSON] et al. [98] has proposed the utilization of a cyclodextrin nanoplex for the co-delivery of 5-fluorouracil (5-FU) and Interleukin-2 (IL-2), creating a chemomomutherapy tool for treating colorectal cancer. The nanoplexes allowed a synergic effect, with enhanced chemotherapeutic and immunotherapeutic activities and diminished side toxicity.