## 3 Nanostructured Systems for Cancer Immunotherapy  
Cancer immunotherapy, which modulates the body's immune system to target tumors, has endowed extended survival in cases previously considered fatal [10; 13]. Combinatorial approaches have particularly been rendered effective for enhancing immunotherapeutic outcomes by targeting multiple pathways within the cancer immunity cycle [64; 65]. Recent advances focus on overcoming tumor-induced immune suppression, with treatments such as immune checkpoint inhibitors (ICIs) targeting CTLA-4, PD-1, and PD-L1 pathways. Such strategies represent valuable alternatives for treating solid and hematological cancers, targeting the evasion mechanisms of the tumor microenvironment [66; 67; 68]. Nonetheless, despite the success demonstrated throughout trials, several challenges remain. ICI-based therapies exhibit limited efficacy due to rapid drug clearance and off-target toxicity, also leading to resistance to immunotherapeutic agents in some patients [12; 13; 68; 69]. While immunotherapy activates the host immune system, it can inadvertently trigger harmful side effects by activating non-tumor-specific immune cells [70]. Increasing evidence has been gathered in cancer immunotherapy regarding the importance of Toll-like receptors (TLRs). TLRs represent a pattern recognition receptor (PRRs) type that can detect pathogen-associated and damage-associated molecular patterns, triggering innate immune responses [10; 15; 71]. Particularly interesting for cancer treatment applications are the TLR7 and TLR8 present on the surface of endosomes. These receptors can induce type 1 interferons and inflammatory responses via the MyD88 pathway [10]. Thus, the administration of TLR agonists, such as imiquimod and resiquimod, can stimulate immune responses and activate cytotoxic T-cells. However, challenges such as poor solubility, side effects, and immune tolerance limit their clinical application. Moreover, the immune system can develop tolerance to TLR activation, over time diminishing the efficacy of TLR7/TLR8 agonist therapeutics [10; 15; 72]. In this context, nanotechnology-based drug delivery approaches have been considered promising solutions to enhance the efficacy of TLR7/8 agonists in cancer immunotherapy. The utilization of various nanocarriers, especially for small molecular immunotherapeutic-quetics, has the potential to mitigate dose-limiting toxicities and enhance treatment outcomes [10; 15; 25]. Nanocarriers, such as nanocapsules, nanoemulsions, and micelles, facilitate targeted delivery, enhance lymphatic transport, and extend drug release, thereby maintaining effective concentrations while reducing toxicity [10]. These nanoparticle engineering advancements enhance cancer cells' targeted absorption and accumulation in cancerous tissues, potentially circumventing existing constraints in immunotherapy and creating mutually beneficial interactions between nanoparticles and immune cells [70; 73]. One interesting possibility for delivering TLR agonists is to use poly(esteracetal)s, as these polymers have the chemical properties necessary for pH-responsive drug release [74]. For instance, [PERSON] et al. [15] developed self-assembling micelles based on amphiphilic mPEG-b-P(MDO) poly(esteracetal) block copolymers (Figure 4) able to carry an immune stimulatory TLR-7 agonist (i.e., Adifectin). This nanosystem allowed the better solubilization of the transported drug, ensuring its efficient delivery, pH-controlled release, and maintenance of receptor activity. On a different note, [PERSON] et al. [75] proposed the utilization of polymeric nanoparticles loaded with imiquimod as an alternative to the commercial drug formulation. The nanoparticles demonstrated significantly greater antiangiogenic activity and reduced tumor size and number compared to the commercial formulation and controls, indicating that the polymeric nanocarriers enhance treatment outcomes by increasing the skin permeation and solubility of the immunotherapeutic cargo for cutaneous malignancies.