Nanoparticulate Delivery of Cancer Cell Membrane Elicits Multiantigenic Antitumor Immunity

Anticancer vaccines train the body's own immune system to recognize and eliminate malignant cells based on differential antigen expression. While conceptually attractive, clinical efficacy is lacking given several key challenges stemming from the similarities between cancerous and healthy tissue. Ideally, an effective vaccine formulation would deliver multiple tumor antigens in a fashion that potently stimulates endogenous immune responses against those antigens. Here, it is reported on the fabrication of a biomimetic, nanoparticulate anticancer vaccine that is capable of delivering autologously derived tumor antigen material together with a highly immunostimulatory adjuvant. The two major components, tumor antigens and adjuvant, are presented concurrently in a fashion that maximizes their ability to promote effective antigen presentation and activation of downstream immune processes. Ultimately, it is demonstrated that the formulation can elicit potent antitumor immune responses in vivo. When combined with additional immunotherapies such as checkpoint blockades, the nanovaccine demonstrates substantial therapeutic effect. Overall, the work represents the rational application of nanotechnology for immunoengineering and can provide a blueprint for the future development of personalized, autologous anticancer vaccines with broad applicability.     

Magnetically Powered Immunogenic Macrophage Microrobots for Targeted Multimodal Cancer Therapy (Small 42/2023)

Motile microrobots open a new realm for disease treatment. However, the concerns of possible immune elimination, targeted capability and limited therapeutic avenue of microrobots constrain its practical biomedical applications. Herein, a biogenic macrophage-based microrobot loaded with magnetic nanoparticles and bioengineered bacterial outer membrane vesicles (OMVs), capable of magnetic propulsion, tumor targeting, and multimodal cancer therapy is reported. Such cell robots preserve intrinsic properties of macrophages for tumor suppression and targeting, and bioengineered OMVs for antitumor immune regulation and fused anticancer peptides. Cell robots display efficient magnetic propulsion and directional migration in the confined space. In vivo tests show that cell robots can accumulate at the tumor site upon magnetic manipulation, coupling with tumor tropism of macrophages to greatly improve the efficacy of its multimodal therapy, including tumor inhibition of macrophages, immune stimulation, and antitumor peptides of OMVs. This technology offers an attractive avenue to design intelligent medical microrobots with remote manipulation and multifunctional therapy capabilities for practical precision treatment.     

Stabilizing RNA Nanovaccines with Transformable Hyaluronan Dynamic Hydrogel for Durable Cancer Immunotherapy

Massage RNA (mRNA) vaccines represent a new strategy for advanced cancer immunotherapy. To protect mRNA from degradation and deliver to targeted cells, lipid nanoparticles (LNPs) are extensively utilized as non-viral vectors. However, the stability of mRNA-laden LNPs substantially hinders their clinical application. Development of thermostable and durable mRNA nanovaccines is urgently needed. Here, a hyaluronan dynamic hydrogel is reported to protect mRNA and resiquimod (R848)-laden LNPs (HA-mRLNPs) from degradation at room temperature for durable cancer immunotherapy. A microfluidic device is proposed to effectively encapsulate mRNA and immunoadjuvants in LNPs (mRLNPs). Then, hyaluronan dynamic hydrogel is used to stabilize LNPs during storage at room temperature by restricting the migration and fusion of LNPs. Particularly, gel-like hyaluronan undergoes state transition for controlled release of mRLNPs under physiological condition. Therefore, HA-mRLNPs can efficiently deliver mRNA encoding tumor antigens to dendritic cells for antigen presentation to induce antigen-specific CD8⁺ T cells for killing tumor cells. Overall, this study demonstrates that the LNPs-hydrogel system can be used for effective cancer immunotherapy.     

Propionibacterium acnes Cloaked with ZnAl Layered Double Hydroxides Synergistically Inhibits Tumor Growth and Metastasis

The combination of precise tumor depletion and immunotherapy presents great potential to exterminate cancer disease. Anaerobic bacteria can trigger innate and adaptive immune responses in tumors to facilitate the antitumor effects. However, bacteria injected intravenously induce systemic inflammation and are likely to be eliminated in the blood. Herein, live bacteria, Propionibacterium acnes (P. acnes), are integrated with ZnAl layered double hydroxides (LDHs) to construct an effective system enabling synergistic inhibition in both tumor growth and metastasis. In this system, P. acnes carries LDHs to reach and penetrate the hypoxic tumor tissue. The metabolism of colonized P. acnes and the pH-responsive degradation of LDHs produce reactive nitrogen species and reactive oxygen species to trigger inevitable cell death. Furthermore, the decomposition of LDHs exposes P. acnes, and thus the immune response is activated to prohibit the reoccurrence of distant tumors. The biohybrid P. acnes@LDHs, developed in this study, possesses remarkable anticancer outcomes both in vitro and in vivo.     

B7 Family Members in Pancreatic Ductal Adenocarcinoma: Attractive Targets for Cancer Immunotherapy

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a five-year survival rate of approximately 5–10%. The immune checkpoint blockade represented by PD-1/PD-L1 inhibitors has been effective in a variety of solid tumors but has had little clinical response in pancreatic cancer patients. The unique suppressive immune microenvironment is the primary reason for this outcome, and it is essential to identify key targets to remodel the immune microenvironment. Some B7 family immune checkpoints, particularly PD-L1, PD-L2, B7-H3, B7-H4, VISTA and HHLA2, have been identified as playing a significant role in the control of tumor immune responses. This paper provides a comprehensive overview of the recent research progress of some members of the B7 family in pancreatic cancer, which revealed that they can be involved in tumor progression through immune-dependent and non-immune-dependent pathways, highlighting the mechanisms of their involvement in tumor immune escape and assessing the prospects of their clinical application. Targeting B7 family immune checkpoints is expected to result in novel immunotherapeutic treatments for patients with pancreatic cancer.     

A Near-Infrared Light-Responsive ROS Cascade Nanoplatform for Synergistic Therapy Potentiating Antitumor Immune Responses

Tumor occurrence is closely related to the unlimited proliferation and the evasion of the immune surveillance. However, it remains a challenge to kill tumor cells and simultaneously activate antitumor immunity upon spatially localized external stimuli. Herein, a robust tumor synergistic therapeutic nanoplatform is designed in combination with dual photosensitizers-loaded upconversion nanoparticles (UCNPs) and ferric-tannic acid (FeTA) nanocomplex. Dual photosensitizers-loaded UCNPs can induce photodynamic therapy (PDT) effect by generation of cytotoxic reactive oxygen species (ROS) on demand under near-infrared (NIR) light irradiation. FeTA can robustly respond to acidic tumor microenvironment to produce Fe²⁺ and subsequently induce chemodynamic therapy (CDT) by reacting with H₂O₂ in the tumor microenvironment. More importantly, the CDT/PDT synergy can not only exhibit significant antitumor ability but also induce ROS cascade to evoke immunogenic cell death. It increases tumor immunogenicity and promotes immune cell infiltration at tumor sites allowing further introduction of systemic immunotherapy responsiveness to inhibit the primary and distant tumor growth. This study provides a potential tumor microenvironment-responsive nanoplatform for imaging-guided diagnosis and combined CDT/PDT with improved immunotherapy responses and an external NIR-light control of photoactivation.     

Controlled Lengthwise Assembly of Helical Peptide Nanofibers to Modulate CD8+ T-Cell Responses

Peptide nanofibers are useful for many biological applications, including immunotherapy, tissue engineering, and drug delivery. The robust lengthwise assembly of these peptides into nanofibers is typically difficult to control, resulting in polydisperse fiber lengths and an incomplete understanding of how nanofiber length affects biological responses. Here, rationally designed capping peptides control the length of helical peptide nanofibers with unique precision. These designed peptides bind the tips of elongated nanofibers to shorten and narrow their length distributions. Demonstrating their use as immunotherapies, capped nanofibers are preferentially cross-presented by dendritic cells compared to uncapped nanofibers. Due to increased cross-presentation, these capped nanofibers trigger stronger CD8⁺ T-cell responses in mice than uncapped nanofibers. This strategy illustrates a means for controlling the length of supramolecular peptide nanofibers to modulate their immunogenicity in the context of immunotherapies.     

Tumor Microenvironment of Hepatocellular Carcinoma: Challenges and Opportunities for New Treatment Options

The prevalence of liver cancer is constantly rising, with increasing incidence and mortality in Europe and the USA in recent decades. Among the different subtypes of liver cancers, hepatocellular carcinoma (HCC) is the most commonly diagnosed liver cancer. Besides advances in diagnosis and promising results of pre-clinical studies, HCC remains a highly lethal disease. In many cases, HCC is an effect of chronic liver inflammation, which leads to the formation of a complex tumor microenvironment (TME) composed of immune and stromal cells. The TME of HCC patients is a challenge for therapies, as it is involved in metastasis and the development of resistance. However, given that the TME is an intricate system of immune and stromal cells interacting with cancer cells, new immune-based therapies are being developed to target the TME of HCC. Therefore, understanding the complexity of the TME in HCC will provide new possibilities to design novel and more effective immunotherapeutics and combinatorial therapies to overcome resistance to treatment. In this review, we describe the role of inflammation during the development and progression of HCC by focusing on TME. We also describe the most recent therapeutic advances for HCC and possible combinatorial treatment options.