The cytokine interleukin-12 (IL-12) is a potential immunotherapy because of its ability to induce a Th1 immune response. However, success in the clinic has been limited due to a phenomenon called IL-12 desensitization - the trend where repeated exposure to IL-12 leads to reduced IL-12 concentrations (pharmacokinetics) and biological effects (pharmacodynamics). Here, we investigated IL-12 pharmacokinetic desensitization via a modeling approach to (i) validate proposed mechanisms in literature and (ii) develop a mathematical model capable of predicting IL-12 pharmacokinetic desensitization. Two potential causes of IL-12 pharmacokinetic desensitization were identified: increased clearance or reduced bioavailability of IL-12 following repeated doses. Increased IL-12 clearance was previously proposed to occur due to the upregulation of IL-12 receptor on T cells that causes increased receptor-mediated clearance in the serum. However, our model with this mechanism, the accelerated-clearance model, failed to capture trends in clinical trial data. Alternatively, our novel reduced-bioavailability model assumed that upregulation of IL-12 receptor on T cells in the lymphatic system leads to IL-12 sequestration, inhibiting the transport to the blood. This model accurately fits IL-12 pharmacokinetic data from three clinical trials, supporting its biological relevance. Using this model, we analyzed the model parameter space to illustrate that IL-12 desensitization occurs over a robust range of parameter values and to identify the conditions required for desensitization. We next simulated local, continuous IL-12 delivery and identified several methods to mitigate systemic IL-12 exposure. Ultimately, our results provide quantitative validation of our proposed mechanism and allow for accurate prediction of IL-12 pharmacokinetics over repeated doses.

Clinically, multimodal therapies are adopted worldwide for the management of cancer, which continues to be a leading cause of death. In recent years, immunotherapy has firmly established itself as a new paradigm in cancer care that activates the body's immune defense to cope with cancer. Immunotherapy has resulted in significant breakthroughs in the treatment of stubborn tumors, dramatically improving the clinical outcome of cancer patients. Multiple forms of cancer immunotherapy, including immune checkpoint inhibitors (ICIs), adoptive cell therapy and cancer vaccines, have become widely available. However, the effectiveness of these immunotherapies is not much satisfying. Many cancer patients do not respond to immunotherapy, and disease recurrence appears to be unavoidable because of the rapidly evolving resistance. Moreover, immunotherapies can give rise to severe off-target immune-related adverse events. Strategies to remove these hindrances mainly focus on the development of combinatorial therapies or the exploitation of novel immunotherapeutic mediations. Nanomaterials carrying anticancer agents to the target site are considered as practical approaches for cancer treatment. Nanomedicine combined with immunotherapies offers the possibility to potentiate systemic antitumor immunity and to facilitate selective cytotoxicity against cancer cells in an effective and safe manner. A myriad of nano-enabled cancer immunotherapies are currently under clinical investigation. Owing to gaps between preclinical and clinical studies, nano-immunotherapy faces multiple challenges, including the biosafety of nanomaterials and clinical trial design. In this review, we provide an overview of cancer immunotherapy and summarize the evidence indicating how nanomedicine-based approaches increase the efficacy of immunotherapies. We also discuss the key challenges that have emerged in the era of nanotechnology-based cancer immunotherapy. Taken together, combination nano-immunotherapy is drawing increasing attention, and it is anticipated that the combined treatment will achieve the desired success in clinical cancer therapy.

Colorectal cancer (CRC) ranks as the third most common cancer worldwide and remains a major cause of cancer-related deaths, necessitating the development of innovative therapeutic approaches beyond conventional treatment modalities. Conventional therapies, such as radiation, chemotherapy, and surgery, are hindered by challenges like imprecise targeting, substantial toxicity, and the development of resistance. Exosome-driven nano-immunotherapy has emerged as a groundbreaking approach that leverages the natural properties of exosomes-cell-derived vesicles known for their role in intercellular communication-to deliver therapeutic agents with high precision and specificity. This approach utilizes the natural ability of exosomes to serve as natural nanocarriers for various biomolecules, such as proteins, nucleic acids, and lipids, enabling precise drug delivery and immune modulation. Exosomes offer distinct advantages compared to traditional drug delivery systems, including their biocompatibility, capability to traverse biological barriers, and suitability for personalized medicine approaches. We evaluate the effectiveness of exosome-based therapies in comparison to traditional approaches, emphasizing their ability to achieve precise delivery, minimize systemic toxicity, and enhance treatment results. Despite their promise, several challenges remain, including the standardization of exosome isolation and production, optimization of cargo loading techniques, and ensuring safety and efficacy in clinical applications. By overcoming these obstacles and leveraging the distinctive characteristics of exosomes, exosome-driven nano-immunotherapy presents a promising avenue for more efficient therapeutic interventions.

Cancer immunotherapy represents a promising targeted treatment by leveraging the patient's immune system or adoptive transfer of active immune cells to selectively eliminate cancer cells. Despite notable clinical successes, conventional immunotherapies face significant challenges stemming from the poor infiltration of endogenous or adoptively transferred cytotoxic T cells in tumors, immunosuppressive tumor microenvironment and the immune evasion capability of cancer cells, leading to limited efficacy in many types of solid tumors. Overcoming these hurdles is essential to broaden the applicability of immunotherapies. Recent advances in nanotherapeutics have emerged as an innovative tool to overcome these challenges and enhance the therapeutic potential of tumor immunotherapy. The unique biochemical and biophysical properties of nanomaterials offer advantages in activation of immune cells in vitro for cell therapy, targeted delivery, and controlled release of immunomodulatory agents in vivo. Nanoparticles are excellent carriers for tumor associated antigens or neoantigen peptides for tumor vaccine, empowering activation of tumor specific T cell responses. By precisely delivering immunomodulatory agents to the tumor site, immunoactivating nanoparticles can promote tumor infiltration of endogenous T cells or adoptively transferred T cells into tumors, to overcoming delivery and biological barriers in the tumor microenvironment, augmenting the immune system's ability to recognize and eliminate cancer cells. This review provides an overview of the current advances in immunotherapeutic approaches utilizing nanotechnology. With a focus on discussions concerning strategies to enhance activity and efficacy of cytotoxic T cells and explore the intersection of engineering nanoparticles and immunomodulation aimed at bolstering T cell-mediated immune responses, we introduce various nanoparticle formulations designed to deliver therapeutic payloads, tumor antigens and immunomodulatory agents for T cell activation. Diverse mechanisms through which nanoparticle-based approaches influence T cell responses by improving antigen presentation, promoting immune cell trafficking, and reprogramming immunosuppressive tumor microenvironments to potentiate anti-tumor immunity are examined. Additionally, the synergistic potential of combining nanotherapeutics with existing immunotherapies, such as immune checkpoint inhibitors and adoptive T cell therapies is explored. In conclusion, this review highlights emerging research advances on activation of cytotoxic T cells using nanoparticle agents to support the promises and potential applications of nanoparticle-based immunomodulatory agents for cancer immunotherapy.

Immunotherapy is an important cancer treatment method that offers hope for curing cancer patients. While immunotherapy has achieved initial success, a major obstacle to its widespread adoption is the inability to benefit the majority of patients. The success or failure of immunotherapy is closely linked to the tumor's immune microenvironment. Recently, there has been significant attention on strategies to regulate the tumor immune microenvironment in order to stimulate anti-tumor immune responses in cancer immunotherapy. The distinctive physical properties and design flexibility of nanomedicines have been extensively utilized to target immune cells (including tumor-associated macrophages (TAMs), T cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated fibroblasts (TAFs)), offering promising advancements in cancer immunotherapy. In this article, we have reviewed treatment strategies aimed at targeting various immune cells to regulate the tumor immune microenvironment. The focus is on cancer immunotherapy models that are based on nanomedicines, with the goal of inducing or enhancing anti-tumor immune responses to improve immunotherapy. It is worth noting that combining cancer immunotherapy with other treatments, such as chemotherapy, radiotherapy, and photodynamic therapy, can maximize the therapeutic effects. Finally, we have identified the challenges that nanotechnology-mediated immunotherapy needs to overcome in order to design more effective nanosystems.

Camptothecin (CPT) is one of the frequently used small chemotherapy drugs for treating hepatocellular carcinoma (HCC), but its clinical application is limited due to severe toxicities and acquired resistance. Combined chemo-gene therapy has been reported to be an effective strategy for counteracting drug resistance while sensitizing cancer cells to cytotoxic agents. Thus, we hypothesized that combining CPT with miR-145 could synergistically suppress tumor proliferation and enhance anti-tumor activity.

Lactobionic acid (LA) modified lipid nanoparticles (LNPs) were developed to co-deliver CPT and miR-145 into asialoglycoprotein receptors-expressing HCC in vitro and in vivo. We evaluated the synergetic antitumor effect of miR-145 and CPT using CCK8, Western blotting, apoptosis and wound scratch assay in vitro, and the mechanisms underlying the synergetic antitumor effects were further investigated. Tumor inhibitory efficacy, safety evaluation and MRI-visible ability were assessed using diethylnitrosamine (DEN) + CCl4-induced HCC mouse model.

The LA modification improved the targeting delivery of cargos to HCC cells and tissues. The LA-CMGL-mediated co-delivery of miR-145 and CPT is more effective on tumor inhibitory than LA-CPT-L or LA-miR-145-L treatment alone, both in vitro and in vivo, with almost no side effects during the treatment period. Mechanistically, miR-145 likely induces apoptosis by targeting SUMO-specific peptidase 1 (SENP1)-mediated hexokinase (HK2) SUMOylation and glycolysis pathways and, in turn, sensitizing the cancer cells to CPT. In vitro and in vivo tests confirmed that the loaded Gd-DOTA served as an effective T1-weighted contrast agent for noninvasive tumor detection as well as real-time monitoring of drug delivery and biodistribution.

The LA-CMGL-mediated co-delivery of miR-145 and CPT displays a synergistic therapy against HCC. The novel MRI-visible, actively targeted chemo-gene co-delivery system for HCC therapy provides a scientific basis and a useful idea for the development of HCC treatment strategies in the future.

The treatment of digestive system tumors presents challenges, particularly in immunotherapy, owing to the advanced immune tolerance of the digestive system. Nanomaterials have emerged as a promising approach for addressing these challenges. They provide targeted drug delivery, enhanced permeability, high bioavailability, and low toxicity. Additionally, nanomaterials target immunosuppressive cells and reshape the tumor immune microenvironment (TIME). Among the various cells in the TIME, tumor-associated macrophages (TAMs) are the most abundant and play a crucial role in tumor progression. Therefore, investigating the modulation of TAMs by nanomaterials for the treatment of digestive system tumors is of great significance. Here, we present a comprehensive review of the utilization of nanomaterials to modulate TAMs for the treatment of gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer. We also investigated the underlying mechanisms by which nanomaterials modulate TAMs to treat tumors in the digestive system. Furthermore, this review summarizes the role of macrophage-derived nanomaterials in the treatment of digestive system tumors. Overall, this research offers valuable insights into the development of nanomaterials tailored for the treatment of digestive system tumors.

Hepatocytes exert pivotal roles in metabolism, protein synthesis and detoxification. Non-parenchymal liver cells (NPCs), largely comprising macrophages, dendritic cells, hepatic stellate cells and liver sinusoidal cells (LSECs), serve to induce immunological tolerance. Therefore, the liver is an important target for therapeutic approaches, in case of both (inflammatory) metabolic diseases and immunological disorders. This review aims to summarize current preclinical nanodrug-based approaches for the treatment of liver disorders. So far, nano-vaccines that aim to induce hepatitis virus-specific immune responses and nanoformulated adjuvants to overcome the default tolerogenic state of liver NPCs for the treatment of chronic hepatitis have been tested. Moreover, liver cancer may be treated using nanodrugs which specifically target and kill tumor cells. Alternatively, nanodrugs may target and reprogram or deplete immunosuppressive cells of the tumor microenvironment, such as tumor-associated macrophages. Here, combination therapies have been demonstrated to yield synergistic effects. In the case of autoimmune hepatitis and other inflammatory liver diseases, anti-inflammatory agents can be encapsulated into nanoparticles to dampen inflammatory processes specifically in the liver. Finally, the tolerance-promoting activity especially of LSECs has been exploited to induce antigen-specific tolerance for the treatment of allergic and autoimmune diseases.

Interleukin-12 (IL-12) demonstrates potent antitumor activity by enhancing Th1/Th2 response, facilitating cytotoxic T-cell (CTL) recruitment into tumors, inhibiting tumor angiogenesis, and depleting immunosuppressive cells in the tumor microenvironment (TME). Despite having encouraging preclinical and some clinical results, further development of IL-12 is limited because dose-limiting toxicity is observed in early clinical trials with systemic administration of recombinant human IL-12. Hence, strategies aiming to lower the toxicity and to improve response rates are unmet needs. In this study, IL-12 was encapsulated in extracellular vesicles derived from mature dendritic cells (DEVs) activated with tumor antigens. IL-12-encapsulated DEVs (DEV-IL) delayed the growth of murine glioblastoma by facilitating the recruitment of CD8 T-cells, NK-cells, and DCs and effectively depleting immunosuppressive cells in the TME. DEV-IL shifted the Th1/Th2 ratio toward dominating Th1 cytokines which further led to the inhibition of angiogenesis. In addition, DEV-IL also modulated systemic immunity by enhancing CTL activity and the levels of proinflammatory cytokines in the spleen. Interestingly, DEV-IL did not impart hepatic and immunotoxicity which was observed with free IL-12 administration. Hence, our study established DEV-IL as a potent platform for the sustained delivery of cytokines and could be a promising immunotherapeutic strategy for the treatment of cancer.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related deaths in the world. However, there are currently few clinical diagnosis and treatment options available, and there is an urgent need for novel effective approaches. More research is being undertaken on immune-associated cells in the microenvironment because they play a critical role in the initiation and development of HCC. Macrophages are specialized phagocytes and antigen-presenting cells (APCs) that not only directly phagocytose and eliminate tumor cells, but also present tumor-specific antigens to T cells and initiate anticancer adaptive immunity. However, the more abundant M2-phenotype tumor-associated macrophages (TAMs) at tumor sites promote tumor evasion of immune surveillance, accelerate tumor progression, and suppress tumor-specific T-cell immune responses. Despite the great success in modulating macrophages, there are still many challenges and obstacles. Biomaterials not only target macrophages, but also modulate macrophages to enhance tumor treatment. This review systematically summarizes the regulation of tumor-associated macrophages by biomaterials, which has implications for the immunotherapy of HCC.

Chitosan is a positively charged polysaccharide obtained through chitin deacetylation. It belongs to a group of biodegradable, bioavailable, and non-toxic materials of natural origin; thus, it is a promising matrix for creating delivery systems of different active agents. Recently, much attention has been paid to nanodelivery systems as carriers to enable better bioavailability, and thus higher efficiency of the loaded drug. The present review is focused on the progress in chitosan-based nanoparticles for the targeted delivery of antitumor drugs. The paper discusses literature reports from the last three years in which chitosan nanoparticles were applied as carriers for active substances used in antitumor therapy and potential new drugs with anticancer properties. Special attention was paid to the different treatments applied to increase the therapeutic effectiveness and minimize the side effects of a specific active substance.

Searching for immunotherapy-related markers is an important research content to screen for target populations suitable for immunotherapy. Prognosis-related genes in early stage lung cancer may also affect the tumor immune microenvironment, which in turn affects immunotherapy.

We analyzed the differential genes affecting lung cancer patients receiving immunotherapy through the Cancer Treatment Response gene signature DataBase (CTR-DB), and set a threshold to obtain a total of 176 differential genes between response and non-response to immunotherapy. Functional enrichment analysis found that these differential genes were mainly involved in immune regulation-related pathways. The early-stage lung adenocarcinoma (LUAD) prognostic model was constructed through the cancer genome atlas (TCGA) database, and three target genes (MMP12, NFE2, HOXC8) were screened to calculate the risk score of early-stage LUAD. The receiver operating characteristic (ROC) curve indicated that the model had good prognostic value, and the validation set (GSE50081, GSE11969 and GSE42127) from the gene expression omnibus (GEO) analysis indicated that the model had good stability, and the risk score was correlated with immune infiltrations to varying degrees. Multi-type survival analysis and immune infiltration analysis revealed that the transcriptome, methylation and the copy number variation (CNV) levels of the three genes were correlated with patient prognosis and some tumor microenvironment (TME) components. Drug sensitivity analysis found that the three genes may affect some anti-tumor drugs. The mRNA expression of immune checkpoint-related genes showed significant differences between the high and low group of the three genes, and there may be a mutual regulatory network between immune checkpoint-related genes and target genes. Tumor immune dysfunction and exclusion (TIDE) analysis found that three genes were associated with immunotherapy response and maybe the potential predictors to immunotherapy, consistent with the CTR-DB database analysis.

From the perspective of data mining, this study suggests that MMP12, NFE2, and HOXC8 may be involved in tumor immune regulation and affect immunotherapy. They are expected to become markers of immunotherapy and are worthy of further experimental research.

With an understanding of immunity in the tumor microenvironment, immunotherapy turns out to be a powerful tool in the clinic to treat many cancers. The strategies applied in cancer immunotherapy mainly include blockade of immune checkpoints, adoptive transfer of engineered cells, such as T cells, natural killer cells, and macrophages, cytokine therapy, cancer vaccines, and oncolytic virotherapy. Many factors, such as product price, off-target side effects, immunosuppressive tumor microenvironment, and cancer cell heterogeneity, affect the treatment efficacy of immunotherapies against cancers. In addition, some treatments, such as chimeric antigen receptor (CAR) T cell therapy, are more effective in treating patients with lymphoma, leukemia, and multiple myeloma rather than solid tumors. To improve the efficacy of targeted immunotherapy and reduce off-target effects, delivery systems for immunotherapies have been developed in past decades using tools such as nanoparticles, hydrogel matrix, and implantable scaffolds. This review first summarizes the currently common immunotherapies and their limitations. It then synopsizes the relative delivery systems that can be applied to improve treatment efficacy and minimize side effects. The challenges, frontiers, and prospects for applying these delivery systems in cancer immunotherapy are also discussed. Finally, the application of these approaches in clinical trials is reviewed.