Nearly 20 million people are diagnosed with cancer each year with breast cancer being the most common among women. Triple negative breast cancer (TNBC), defined by its no/low expression of ER and PR and lack of amplification of HER2, makes up 15-20% of all breast cancer cases. While patients overall have a higher response to chemotherapy, this subgroup is associated with the lowest survival rate indicating significant clinical and molecular heterogeneity demanding alternate treatment options. Therefore, new therapies have been explored, with a large focus on utilizing the immune system. A whole host of immunotherapies have been studied including immune checkpoint inhibitors, now standard of care for eligible patients, and possibly the most exciting and promising is that of a TNBC vaccine. While currently there are no approved TNBC vaccines, this review highlights many promising studies and points to an antigen, p53, which we believe is highly relevant for TNBC.

Among the plethora of cancer immune evasion mechanisms, T-cell-inhibiting factors within the tumor microenvironment impose a major challenge for the development of novel immunotherapies. Strategies to overcome immunosuppression and remodel the TME are therefore urgently needed. Therapeutic cancer vaccines based on engineered arenaviruses have been proven to generate potent tumor specific CD8+ T-cell responses in preclinical models and cancer patients. Despite signs of clinical activity as monotherapy, combination therapies are needed to further increase the therapeutic effect. To address this need, we evaluated the efficacy of recombinant vectors based on lymphocytic choriomeningitis virus encoding the T-cell stimulating cytokines IL-7, IL-12 and IL-15 with or without tumor-associated antigens. These vectors were tested in three different mouse tumor models (TC-1, MC-38 and B16.F10). Our results demonstrate that only IL-12 encoding vectors led to increased immunogenicity and efficacy, which, after systemic administration, was associated with adverse events. The safest and most potent regimen consisted of systemic vaccination with tumor antigen encoding vectors and local injection of IL-12-encoding vectors. A single round of this treatment regimen resulted in 86-100% tumor-free mice and warrants further investigation.

The treatment of advanced prostate cancer (PCa) primarily based on androgen deprivation therapy (ADT); however, patients inevitably progress to the castration-resistant prostate cancer (CRPC) stage. Despite the recent advancements in CRPC treatment with novel endocrine drugs that further inhibit androgen receptor signaling, resistance ultimately develops, underscoring the urgent need for new effective therapeutic strategies. Therapeutic cancer vaccines, a form of immunotherapy, exert anti-cancer effects by activating the host's immune system. Over the past few decades, various conventional therapeutic PCa vaccines based on cells, microbes, proteins, peptides, or DNA have been developed and tested in patients with advanced PCa. These attempts have largely failed to improve survival, with the sole exception of sipuleucel-T, which extended the median overall survival of asymptomatic or minimally symptomatic metastatic CRPC (mCRPC) patients by four months. The rapid development and high efficacy of mRNA vaccines during the COVID-19 pandemic have garnered worldwide attention. Compared to conventional vaccines, mRNA vaccines offer several unique advantages, including high production efficiency, low cost, high safety, strong immune response induction, and high adaptability and precision. These attributes make mRNA vaccines a promising frontier in the treatment of advanced PCa.

Colorectal cancer (CRC) is a leading health issue and treatments to eradicate it, such as conventional chemotherapy, are non‑selective and come with a number of complications. The present review focuses on the relatively new area of precision oncolytic viral therapy (OVT), with genetic targeting and immune modifications that offer a new future for CRC treatment. In the present review, an overview of the selection factors that are considered optimal for an oncolytic virus, mechanisms of oncolysis and immunomodulation applied to the OVT, as well as new strategies to improve the efficacy of this method are described. Additionally, cause‑and‑effect relationships are examined for OVT efficacy, mediated by the tumor microenvironment, and directions for genetic manipulation of viral specificity are explored. The possibility of synergy between OVT and immune checkpoint inhibitors and other treatment approaches are demonstrated. Incorporating the details of the present review, biomarker‑guided combination therapies in precision OVT for individualized CRC care, significant issues and future trends in this required area of medicine are highlighted. Increasingly, OVT is leaving the experimental stage and may become routine practice; it provides a new perspective on overcoming CRC and highlights the importance of further research and clinical work.

Bladder cancer (BLCA) remains a significant global health concern, being characterized by high incidence, recurrence, and mortality rates. Disease heterogeneity and rapid progression pose major challenges for effective management and identification of actionable biomarkers. Conventional therapies often fail to successfully achieve disease control, urging the development of novel, personalized approaches. In recent years, anti-tumour immunotherapy approaches in both pre-clinical and clinical settings have boomed. However, the efficacy of these strategies has been limited by the low mutational burden in some tumours, which hinders neoantigen presentation and the identification of BLCA-specific signatures. Cancer-associated aberrant glycosylation presents a unique opportunity for identifying BLCA-specific glycosignatures and developing innovative targeted therapeutics. This review provides a comprehensive overview of the clinical challenges in BLCA management and emerging novel therapies. Furthermore, it highlights the potential of glycosylation alterations as a unique opportunity for developing glycan-based therapies, potentially revolutionizing BLCA treatment strategies.

Human papillomavirus (HPV)-associated cancers remain a critical health challenge, prompting the development of effective therapeutic vaccines. This study presents a lipid nanoparticle (LNP)-based vaccine co-loading E7 antigen peptide and magnesium ions as the adjuvant. Microfluidic technology was employed to optimize LNP preparation and formulation, ensuring efficient co-delivery of antigen and adjuvant. Magnesium ions were chosen over conventional aluminum-based adjuvants, which often suffer from limited efficacy and adverse effects, particularly for cancer immunotherapy. Compared to aluminum, magnesium ions exhibited superior capabilities in enhancing T-cell activation and promoting cellular immune response. Mechanistic insights suggest that magnesium ions facilitate dendritic cell maturation and antigen presentation via a collagen-CD36 axis, contributing to the adjuvant activity of magnesium. Through design of experiments (DoE) optimization, the LNP formulation was tailored for enhanced encapsulation and stability, positioning it as a targeted system for immune activation. These findings support the promise of magnesium ions as effective and safer adjuvants in LNP-based vaccines, marking a potential advancement for therapeutic cancer vaccination.

Colorectal cancer (CRC) is among the foremost causes of cancer-related mortality worldwide; however, individuals with microsatellite-stable (MSS) disease-who constitute most CRC diagnoses-derive limited benefit from existing immunotherapeutic approaches. Here, we outline emerging methods designed to address the inherent resistance of MSS CRC to immune checkpoint inhibitors (ICIs). Recent findings emphasize how the immunosuppressive tumor microenvironment (TME) in MSS CRC, marked by diminished immunogenicity and high levels of regulatory T cells and myeloid-derived suppressor cells, restricts effective antitumor immune activity. Combination regimens that merge ICIs with chemotherapy, anti-angiogenic agents, or targeted blockade of pathways such as TGF-β and VEGF have shown encouraging early outcomes, including enhanced antigen presentation and T-cell penetration. Novel immunomodulatory platforms-such as epigenetic modifiers, oncolytic viruses, and engineered probiotic vaccines-are under assessment to further reprogram the TME and boost therapeutic efficacy. Concurrently, progress in adoptive cell therapies (for example, chimeric antigen receptor (CAR) T cells) and the development of cancer vaccines targeting tumor-associated and neoantigens promise to extend immune control over MSS CRC. In parallel, improving patient selection through predictive biomarkers-from circulating tumor DNA (ctDNA) to gene expression signatures and specific molecular subtypes-could refine individualized treatment strategies. Finally, interventions that alter the gut microbiome, including probiotics and fecal transplantation, serve as complementary tools to strengthen ICI responses. Taken together, these insights and combined treatment strategies lay the foundation for more successful immunotherapeutic interventions in MSS CRC, ultimately aiming to provide sustained clinical benefits to a broader spectrum of patients.

Protein-based vaccines are gaining attention as a promising platform for vaccines because they are highly safe and induce humoral and cellular immunity. However, antigenic proteins have the disadvantages of low cell membrane permeability and easy degradability by endo/lysosomes. Therefore, the development of carriers that can overcome these challenges is essential. We recently developed a supramolecular carrier for the intracellular delivery of genome-editing molecules using cyclodextrin-based aminated polyrotaxanes (amino-PRX). The amino-PRX deformed its structure in response to the complicated shape and charge distribution of the genome-editing molecule, forming a complex with high efficiency. Moreover, by optimizing its structure, a second-generation amino-PRX (2G) possessing endosomal escape ability was constructed. Considering 2G deformability, it is applicable to antigenic proteins and could be an excellent antigen carrier. Therefore, here, we aimed to evaluate the utility of 2G as a protein-based cancer vaccine carrier. The results showed that 2G formed complexes with antigenic proteins efficiently. In addition, the 2G/antigenic protein complex activated immune cells with high efficiency and exhibited excellent antitumor effects. These results suggest that 2G is a promising protein-based cancer vaccine carrier.

Recent advancements in immunotherapy, particularly Chimeric antigen receptor (CAR)-T cell therapy and cancer vaccines, have significantly transformed the treatment landscape for leukemia. CAR-T cell therapy, initially promising in hematologic cancers, faces notable obstacles in solid tumors due to the complex and immunosuppressive tumor microenvironment. Challenges include the heterogeneous immune profiles of tumors, variability in antigen expression, difficulties in therapeutic delivery, T cell exhaustion, and reduced cytotoxic activity at the tumor site. Additionally, the physical barriers within tumors and the immunological camouflage used by cancer cells further complicate treatment efficacy. To overcome these hurdles, ongoing research explores the synergistic potential of combining CAR-T cell therapy with cancer vaccines and other therapeutic strategies such as checkpoint inhibitors and cytokine therapy. This review describes the various immunotherapeutic approaches targeting leukemia, emphasizing the roles and interplay of cancer vaccines and CAR-T cell therapy. In addition, by discussing how these therapies individually and collectively contribute to tumor regression, this article aims to highlight innovative treatment paradigms that could enhance clinical outcomes for leukemia patients. This integrative approach promises to pave the way for more effective and durable treatment strategies in the oncology field. These combined immunotherapeutic strategies hold great promise for achieving more complete and lasting remissions in leukemia patients. Future research should prioritize optimizing treatment sequencing, personalizing therapeutic combinations based on individual patient and tumor characteristics, and developing novel strategies to enhance T cell persistence and function within the tumor microenvironment. Ultimately, these efforts will advance the development of more effective and less toxic immunotherapeutic interventions, offering new hope for patients battling this challenging disease.

Cancer is one of the leading causes of mortality worldwide. Nanomedicines have significantly improved life expectancy and survival rates for cancer patients in current standard care. However, recurrence of cancer due to metastasis remains a significant challenge. Vaccines can provide long-term protection and are ideal for preventing bacterial and viral infections. Cancer vaccines, however, have shown limited therapeutic efficacy and raised safety concerns despite extensive research. Cancer vaccines target and stimulate responses against tumor-specific antigens and have demonstrated great potential for cancer treatment in preclinical studies. However, tumor-associated immunosuppression and immune tolerance driven by immunoediting pose significant challenges for vaccine design. In situ vaccination represents an alternative approach to traditional cancer vaccines. This strategy involves the intratumoral administration of immunostimulants to modulate the growth and differentiation of innate immune cells, such as dendritic cells, macrophages, and neutrophils, and restore T-cell activity. Currently approved in situ vaccines, such as T-VEC, have demonstrated clinical promise, while ongoing clinical trials continue to explore novel strategies for broader efficacy. Despite these advancements, failures in vaccine research highlight the need to address tumor-associated immune suppression and immune escape mechanisms. In situ vaccination strategies combine innate and adaptive immune stimulation, leveraging tumor-associated antigens to activate dendritic cells and cross-prime CD8+ T cells. Various vaccine modalities, such as nucleotide-based vaccines (e.g., RNA and DNA vaccines), peptide-based vaccines, and cell-based vaccines (including dendritic, T-cell, and B-cell approaches), show significant potential. Plant-based viral approaches, including cowpea mosaic virus and Newcastle disease virus, further expand the toolkit for in situ vaccination. Therapeutic modalities such as chemotherapy, radiation, photodynamic therapy, photothermal therapy, and Checkpoint blockade inhibitors contribute to enhanced antigen presentation and immune activation. Adjuvants like CpG-ODN and PRR agonists further enhance immune modulation and vaccine efficacy. The advantages of in situ vaccination include patient specificity, personalization, minimized antigen immune escape, and reduced logistical costs. However, significant barriers such as tumor heterogeneity, immune evasion, and logistical challenges remain. This review explores strategies for developing potent cancer vaccines, examines ongoing clinical trials, evaluates immune stimulation methods, and discusses prospects for advancing in situ cancer vaccination.

The development of effective vaccines requires a rational design that considers the interaction between antigens, their vectors, and the immune system in addition to the activation of pathways that induce a safe and specific immune response. The efficacy of a vaccine formulation depends on the nature of the antigen, the protection offered by the delivery system, the ability to potentiate the immune response, and the precise release of the immunogen. Carrier systems such as lipid nanoparticles, polymers, exosomes, and microorganisms can be functionalized by chemical, physical, or biological methods to generate selective and improved biodistribution profiles. These methods enhance interaction with target cells, thereby improving immunological efficacy. The conjugation of specific ligands or the modification of parameters such as shape, charge, and size of vectors can enhance the specificity, stability, and efficiency of antigen transport to cellular compartments, thereby facilitating a robust immune response. This study examines modifications in vaccine delivery systems, focusing on biomolecules and physicochemical changes that enhance antigen presentation. Additionally, we examine innovative methods, including microneedles, electroporation, and needle-free systems that show potential for enhancing the immune response.

Colorectal cancer (CRC), the third most common cancer worldwide, is one of the deadliest cancers. CRC is known as a cold tumor, characterized by a low immune response that makes it difficult for immune cells to infiltrate and exhibits strong resistance to immunotherapy with checkpoint inhibition. This restricted response is largely attributed to signature gene mutations including mismatch repair (MMR) genes, KRAS, BRAF, APC, and TP53, which are also the main oncogenes in CRC. Mutated signature genes continuously upregulate abnormal signaling pathways, leading to excessive proliferation, cancer progression, and metastasis. Furthermore, it reorganizes the tumor microenvironment (TME) by recruiting immunosuppressive cells. However, the mutation can produce neoantigens that can provoke an immune response, making it a potential target for immunotherapy. In particular, cancer vaccines that leverage the strong neoantigenic properties of these mutations are considered promising for overcoming immune resistance and eliciting anti-tumor responses. In this review, we will describe signature gene mutations in CRC and focus on cancer vaccines targeting these mutations as potential therapies for CRC.

Malignant melanoma is a cancer that develops from melanocytes in the skin and mucous membranes. Surgery, and chemotherapy, radiation therapy, or immunotherapy are also used in cases of distant metastasis. Immunotherapy includes immune checkpoint inhibitors and cancer vaccine therapy; however, their efficacy remains limited.

A systematic review and meta-analysis of cancer vaccine therapies were conducted. PubMed was used to search the literature up to December 2023, and clinical trials were also identified for the same period. RCTs involving patients with resectable or unresectable malignant melanoma were included. The primary outcome was OS, and secondary outcomes were PFS, DFS, and RFS. Safety was assessed based on AEs. Integrated results were presented as risk ratio and risk difference.

The initial search identified 418 studies on cancer vaccine therapy and 44 studies on effector T-cell therapy. We supplemented this with our PubMed search, extracting 149 studies. After database searches and screening, 611 studies were initially considered. Following exclusions based on eligibility criteria, 20 RCTs using cancer vaccines remained. For the primary outcome, OS, the pooled RR was 1.11 (95% CI, 0.97-1.32, I2 = 59.0%), and the pooled RD was 0.02 (-0.01 to 0.06, I2 = 74.0%) at 12 months. PFS, DFS, and RFS did not show statistically significant differences, and AEs did not increase significantly.

Cancer vaccine therapy, neither alone, or in combination with other agents for malignant melanoma did not show a significant improvement in OS, PFS, DFS, or RFS nor did it significantly increase AEs.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Conventional therapies are frequently limited by tumor heterogeneity and the immunosuppressive tumor microenvironment (TME). Dendritic cells (DCs), central to orchestrating antitumor immunity, have become key targets for HCC immunotherapy. This review examines the biological functions of DC subsets (cDC1, cDC2, pDC, and moDC) and their roles in initiating and modulating immune responses against HCC. We detail the mechanisms underlying DC impairment within the TME, including suppression by regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs). Additionally, we discuss novel DC-based therapeutic strategies, such as DC-based vaccines designed to enhance antigen presentation and T cell activation. Combining DC vaccines with immune checkpoint inhibitors (ICIs), including PD-1/PD-L1 and CTLA-4 blockers, demonstrates synergistic effects that can overcome immune evasion and improve clinical outcomes. Despite progress, challenges related to DC subset heterogeneity, TME complexity, and patient variability require the further optimization and personalization of DC-based therapies. Future research should focus on refining these strategies, leveraging advanced technologies like genomic profiling and artificial intelligence, to maximize therapeutic efficacy and revolutionize HCC treatment. By restoring DC function and reprogramming the TME, DC-based immunotherapy holds immense potential to transform the management of HCC and improve patient survival.

Despite significant advancements in cancer treatment, current therapies often fail to completely eradicate malignant cells. This shortfall underscores the urgent need to explore alternative approaches such as cancer vaccines. Leveraging the immune system's natural ability to target and kill cancer cells holds great therapeutic potential. However, the development of cancer vaccines is hindered by several challenges, including low stability, inadequate immune response activation, and the immunosuppressive tumor microenvironment, which limit their efficacy. Recent progress in various fields, such as click chemistry, nanotechnology, exosome engineering, and neoantigen design, offer innovative solutions to these challenges. These achievements have led to the emergence of smart vaccine platforms (SVPs), which integrate protective carriers for messenger ribonucleic acid (mRNA) with functionalization strategies to optimize targeted delivery. Click chemistry further enhances SVP performance by improving the encapsulation of mRNA antigens and facilitating their precise delivery to target cells. This review highlights the latest developments in SVP technologies for cancer therapy, exploring both their opportunities and challenges in advancing these transformative approaches.

Tumor vaccines have shown great promise for treating various malignancies; however, glioblastoma (GBM), characterized by its immunosuppressive tumor microenvironment, high heterogeneity, and limited accessibility, has achieved only modest clinical benefits. Here, it is reported that GBM cell lysate nanovaccines boosted with TLR9 agonist CpG ODN (GlioVac) via a strategic vaccination regimen achieve complete regression of malignant murine GBM tumors. Subcutaneous administration of GlioVac promotes uptake by cervical lymph nodes and antigen presentation cells, bolstering antigen cross-presentation and infiltration of GBM-specific CD8+ T cells into the tumor. Notably, a regimen involving two subcutaneous and three intravenous vaccinations not only activates systemic anti-GBM immunity but also further enhances the tumor infiltration of cytotoxic T lymphocytes, effectively reshaping the "cold" GBM tumor into a "hot" tumor. This approach led to a state of tumor-free survival in 5 out of 7 mice bearing the established GL261 GBM model with complete protection from tumor rechallenge. In an orthotopic hRas-GBM model induced by a lentiviral plasmid, GlioVac resulted in ≈100% complete tumor regression. These findings suggest that GlioVac provides a personalized therapeutic vaccine strategy for glioblastoma.

Checkpoint inhibitor therapies do not benefit all patients, and adjuvants play a critical role in boosting immune responses for effective cancer immunotherapy. However, their systemic toxicity and suboptimal activation kinetics pose significant challenges. Here, this study presented a linker-based strategy to modulate the activation kinetics of Toll-like receptor 7/8 (TLR7/8) agonists delivered via poly (propylene sulfide) nanoparticles (PPS NPs). By covalently binding small molecule TLR7/8 agonists to PPS NPs with different linkers, enhanced therapeutic efficacy is achieved while abrogating systemic toxicity. These results showed that an alkyl linker selectively prolong the activation of DCs. It avoided the extensive activation of other APCs, favoring the limitation of immune-related toxicities. This strategy exhibited significant anti-tumor activity in alkyl linked nano-TLR7/8 agonists treatment alone, and cytokine and immune cell profiling provided evidence of prolonged immune cell activation in the tumor microenvironment, with evidence of an increase in the frequency of tumor antigen-specific CD8+ T cells. This linker-based approach offers a promising strategy to optimize the delivery of nano-TLR7/8 agonists for cancer immunotherapy, potentially advancing the field toward improved clinical outcomes.

Glioma is the most common primary brain tumor, with glioblastoma being the most lethal type due to its heterogeneous and invasive nature of the cancer. Current therapies have low curative success and are limited to surgery, radiotherapy, and chemotherapy. More than 50% of patients become resistant to chemotherapy, and tumor recurrence occurs in most patients following an initial course of therapy. Therefore, developing novel, effective strategies for glioma treatment is essential. Cancer vaccines are novel therapies that demonstrate advantages over conventional methods and, therefore, may be promising options for treating glioma.

This article provided a critical review of pre-clinical and clinical studies that explored appropriate tumor antigen candidates for developing mRNA vaccines and discussed their clinical application in glioma patients. Medline database, PubMed, and ClinicalTrials.gov were searched for glioma vaccine studies published before 2025 using related keywords.

mRNA vaccines are promising strategies for treating glioma because they are efficient, cost-beneficial, and have lower side effects than other types such as peptide or DNA-based vaccines.

Immuno-oncology (IO) is one of the fastest growing therapeutic areas within oncology. IO agents work indirectly via the host's adaptive and innate immune system to recognize and eradicate tumor cells. Despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product category. Current Food and Drug Administration (FDA)-approved classes of IO agents include: immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy (CAR-T), bi-specific T-cell engager (BiTE) antibody therapy, T-cell receptor (TCR) engineered T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, cytokine therapy, cancer vaccine therapy, and oncolytic virus therapy. Cancer immunotherapy has made progress in multiple cancer types including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma; however, several cancers remain refractory to immunotherapy. Future directions of IO include exploration in the neoadjuvant/perioperative setting, combination strategies, and optimizing patient selection through improved biomarkers.

Cancer vaccines show promise by eliciting tumor-specific cytotoxic T lymphocytes (CTL) responses. Efficient cytosolic co-delivery of antigens and adjuvants to dendritic cells (DCs) is crucial for vaccines to induce anti-tumor immunity. However, peptide- or nucleic acid-based biomolecules like tumor antigens and STING agonist cyclic-di-GMP (cdGMP) are prone to endosomal degradation, resulting in low cytosolic delivery and CTL response rates. Cationic nanocarriers can improve cytosolic delivery, but their positive charges induce off-target effects. Here, we develop cationic poly(ester amide) based nanoparticles co-loaded with antigens and adjuvant cdGMP (NP(cG, OVA)) for efficient cytosolic delivery and swallow them within antigen self-presenting DCs-derived dendrosomes (ODs) for lymph nodes (LNs) homing. The constructed dendrosomes swallowing nanovaccines ODs/NP(cG, OVA) demonstrated significantly reduced liver accumulation and enhanced LNs and DCs targeting compared to NP(cG, OVA). ODs/NP(cG, OVA) effectively cross-dressed the antigen epitopes on the shell to DCs and facilitated internalization of NP(cG, OVA), realizing DCs cytosolic co-delivery of antigens and adjuvants, thereby promoting antigen presentation, maturation and inflammatory cytokines secretion of DCs. Consequently, DCs stimulated by ODs/NP(cG, OVA) effectively induced activation, proliferation, and differentiation of antigen-specific CTLs that provided robust immune protection against tumor invasion. This work presents a powerful vaccine strategy for cancer immunotherapy.

Nanotechnology has revolutionized cancer treatment by providing innovative solutions through nanocancer therapies, nanovaccines, and nanoparticles. This review focuses on the application of these technologies in colorectal cancer (CRC), highlighting their progression from preclinical studies to clinical trials. Nanoparticles, including liposomes, silica, gold, and lipid nanoparticles, possess unique properties that enhance drug delivery, improve therapeutic efficacy, and minimize systemic toxicity. Additionally, nanovaccines are being developed to elicit robust immune responses against CRC cells. This paper offers a comprehensive overview of the current state of nanotechnology-based treatments for CRC, emphasizing key preclinical studies and clinical trials that demonstrate their potential. Furthermore, the review discusses the challenges faced in this field. It outlines future directions for research, underscoring the need for ongoing efforts to translate these promising technologies into practical clinical applications.

In cancer therapy, tumor cells can diminish their signals through mechanisms such as immune escape, thereby evading recognition and elimination by the immune system. Providing tumor signals to enhance the recognition of tumor sites is considered a crucial approach in cancer treatment. Inspired by the decoy-induced directed feeding of fish, we propose a biomimetic nanoparticle system for tumor signal amplification. This biomimetic system comprises magnetically responsive nanoparticles and immune-inducing bacterial membranes. These designs work together to create a baiting effect at the tumor site, attracting and activating immune cells to attack. It has been demonstrated that the generated nanoparticles have the potential to be targeted and delivered to the tumor site under the influence of an external magnetic field, as demonstrated in preliminary in vitro and in vivo studies. Moreover, the nanoparticles utilize the bacterial membrane and cell membrane-translocated calreticulin to induce an immune response, simulating a decoy mechanism to recruit immune cells. The nanoparticles were proved to be effective in recruiting macrophages and neutrophils and reducing tumor size in animal experiments. These features make the nanoparticles an ideal candidate for treating tumors.

Porphyrin and its derivatives are widely used in cancer therapy due to their strong photon absorption capabilities and moderate light stability. Due to their hydrophobic nature, porphyrins with tetrapyrrolic macrocycles ease self-aggregation in physiological conditions. Instead, exploiting the C4 symmetry structure for self-assembly is beneficial to improve the bioavailability of porphyrin and its derivatives. Herein, this Review outlines porphyrin-based nanoformulations for therapeutic applications in cancer treatment. The typical pharmaceutical application of the integrated porphyrinic structure is systematically summarized, focusing on the typical synthetic methodologies and structure-functionality relationship. Additionally, therapeutic modalities (e.g., photothermal, photodynamic, and sonodynamic) and their synergy mechanism in regulated cell death are overviewed. Special attention is given to emerging technologies in nanocatalytic therapy, therapeutic vaccines, and proteolysis-targeting chimeras, which align with the trend toward personalization and minimal invasiveness in healthcare. Finally, we discuss the challenges and limitations of porphyrinic nanoformulations and explore their future directions in the healthcare sector, aiming to bridge the gap between research and practical clinical application.

Messenger RNA (mRNA) vaccines have emerged as one of the most promising and rapidly evolving immunotherapeutic approaches due to their ease of production, demonstrated clinical efficacy, and high safety. The coronavirus disease 2019(COVID-19) pandemic has showcased the remarkable therapeutic potential of mRNA vaccines, prompting researchers to explore their use for cancer treatment. Preclinical studies and human clinical trials have indicated their substantial clinical applicability. However, current research faces several challenges, including the complexity of tumor antigen selection, vaccine stability, and the development of resistance. This review summarizes the optimization strategies for cancer mRNA vaccines in preclinical settings, the progress of clinical trials, and the challenges encountered while analyzing various delivery vehicle types, infusion methods, and application cases across different cancer types, highlighting key factors in vaccine design. The findings demonstrate that mRNA vaccines elicit specific immune responses and exhibit favorable safety and tolerability in clinical trials. Moreover, developing personalized neoantigen vaccines offers a novel direction for cancer immunotherapy. The unique contribution of this review lies in its comprehensive overview of the latest advancements in therapeutic mRNA vaccines for cancer treatment while identifying critical areas for future research to propel the field forward.

Rationale: Induced pluripotent stem cells (iPSCs) share transcriptomic similarities with cancer cells and express tumor-specific and tumor-associated antigens, highlighting their potential as cancer vaccines. Our previous study demonstrated that an iPSC-based vaccine effectively prevented tumor growth in various mouse models, including melanoma, breast, lung, and pancreatic cancers. However, the underlying mechanisms and the therapeutic efficacy of the iPSC-based vaccine remain unclear. Colorectal cancer (CRC), the third most common cancer with a rising incidence worldwide, presents an urgent need for novel strategies to prevent and treat CRC. Methods: Allograft mouse models were established to evaluate the antitumor effects of the iPSC-based vaccine. CpG oligonucleotide (ODN) 1826 served as a vaccine adjuvant. Bulk RNA-Sequencing (RNA-Seq) and the Microenvironment Cell Population counter (MCP-Counter) algorithm were performed to analyze transcriptomic changes. Liquid chromatography-mass spectrometry (LC-MS) combined with in silico strategies was employed to identify potential antigen proteins. Chinese Hamster Ovary (CHO-K1) models were utilized to express candidate neoantigen proteins. Mouse bone marrow-derived dendritic cells (BMDCs) were used to investigate T cell priming in response to iPSC-associated proteins. Immune cell profiles were characterized by flow cytometry. Results: The combination of CpG and iPSC vaccination demonstrated both prophylactic and therapeutic efficacy in reducing tumor growth in CRC mouse models. Vaccination significantly increased CD8+ T cell infiltration within tumor regions, while T cell depletion abrogated the antitumor effects, underscoring the critical role of T cells in mediating these responses. Proteomic analysis identified two iPSC-associated proteins, heterogeneous nuclear ribonucleoprotein U (HNRNPU) and nucleolin (NCL), as key drivers of the observed immune responses. Vaccination with HNRNPU or NCL, in combination with CpG, enhanced dendritic cell activation, induced antigen-specific CD8+ T cell cytotoxicity, and promoted the formation of central memory CD8+ T cells, collectively leading to significant CRC tumor shrinkage. Conclusions: Our findings reveal potential mechanisms underlying the efficacy of iPSC-based vaccines in cancer immunotherapy. Additionally, HNRNPU and NCL were identified as key antigen proteins in iPSC, demonstrating promise for the development of peptide-based vaccines for both the prevention and treatment of CRC.

Neoantigen-based immunotherapy has emerged as a transformative approach in cancer treatment, offering precision medicine strategies that target tumor-specific antigens derived from genetic, transcriptomic, and proteomic alterations unique to cancer cells. These neoantigens serve as highly specific targets for personalized therapies, promising more effective and tailored treatments. The aim of this article is to explore the advances in neoantigen-based therapies, highlighting successful treatments such as vaccines, tumor-infiltrating lymphocyte (TIL) therapy, T-cell receptor-engineered T cells therapy (TCR-T), and chimeric antigen receptor T cells therapy (CAR-T), particularly in cancer types like glioblastoma (GBM). Advances in technologies such as next-generation sequencing, RNA-based platforms, and CRISPR gene editing have accelerated the identification and validation of neoantigens, moving them closer to clinical application. Despite promising results, challenges such as tumor heterogeneity, immune evasion, and resistance mechanisms persist. The integration of AI-driven tools and multi-omic data has refined neoantigen discovery, while combination therapies are being developed to address issues like immune suppression and scalability. Additionally, the article discusses the ongoing development of personalized immunotherapies targeting tumor mutations, emphasizing the need for continued collaboration between computational and experimental approaches. Ultimately, the integration of cutting-edge technologies in neoantigen research holds the potential to revolutionize cancer care, offering hope for more effective and targeted treatments.

Therapeutic cancer vaccines are an emerging class of immunotherapy, but challenges remain in effectively adapting approved vaccines to a growing number of adjuvants, combination therapies, and antigen-selection methods. Phase III clinical trials remain the gold standard in determining clinical benefit, but are slow and resource intensive, whilst radiological surrogates often fail to reliably predict clinical benefit. Using immunological surrogates of efficacy, deployed in 'immunobridging trials', could present a viable alternative, safely speeding up cancer vaccine development in a cost-effective manner. Whilst this approach has proven successful in infectious disease vaccines, identifying reliable immunological correlates of protection has proven difficult for cancer vaccines. Most clinical trials, which present the richest source of data to establish a correlate, rely on peripheral blood samples and standard immunoassays that are ill-equipped to capture the complexity of the vaccine-induced anti-tumour response. This review is the first to outline the importance and challenges of establishing immunological surrogates for cancer vaccines in the context of immunobridging trials, evaluating current immunoassay methods, and highlighting the need for techniques that can characterize tumour-infiltrating lymphocytes and the suppressive tumour microenvironment across a range of patients. The authors propose adapting trial designs for surrogate discovery, including combining phase I/II trials and the use of multi-omics approaches. Successful immunological surrogate development could enable future immunobridging trials to accelerate the optimization of approved cancer vaccines without requiring new phase III trials, promoting faster clinical implementation of scientific advances and patient benefits.

Alisertib is a potent aurora A kinase inhibitor in clinical trials for cancer treatment, but its efficacy on cancer vaccines remains unclear. Here, we developed a DNA vaccine targeting glypican-3 (pGPC3) and evaluated its efficacy with alisertib in hepatocellular carcinoma (HCC) models. The combination therapy of pGPC3 vaccine and alisertib significantly inhibited subcutaneous tumor growth, enhanced the induction and maturation of CD11c+ and CD8+CD11c+ dendritic cells (DCs), and expanded tumor-specific CD8+ T cell responses. CD8+ T cell depletion abolished the anti-tumor effects, underscoring the essential role of functional CD8+ T cell responses. Moreover, the combined treatment promoted memory CD8+ T cell induction, providing long-term protection. In liver orthotopic tumor models, the combination of pGPC3 vaccine and alisertib demonstrated potent therapeutic efficacy through CD8+ T cell responses. These results indicate that alisertib enhances the pGPC3 vaccine's therapeutic effect, offering a promising strategy for HCC treatment.

Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein overexpressed in various cancers and associated with poor prognosis. Despite the success of TROP2-targeting antibody-drug conjugates (ADCs), challenges such as high molecular weight, linker instability, and complex manufacturing limit their broader application. To address these limitations, we developed a novel immunotoxin, Fab-PE24, by conjugating the Fab fragment of a humanized anti-TROP2 monoclonal antibody with a truncated Pseudomonas aeruginosa exotoxin A (PE24KDEL) using SpyCatcher-SpyTag technology. Fab-PE24 demonstrated high binding affinity to both recombinant and native TROP2 antigens, efficient internalization, and potent cytotoxicity, inducing apoptosis and inhibiting proliferation in TROP2-positive cancer cells. In vivo, Fab-PE24 significantly suppressed tumor growth in gastric and lung cancer xenograft models. Notably, Fab-PE24 exhibited synergistic antitumor effects when combined with cisplatin, suggesting its potential for overcoming chemotherapy resistance. This study presents a novel modular approach for constructing PE-based immunotoxins and highlights Fab-PE24 as a promising therapeutic candidate for TROP2-positive malignancies.

Inactivated whole tumor cell-based vaccines (WTVs) are a promising strategy for tumor immunotherapy, but have exhibited limited antitumor effects clinically. Aiming at constructing enhanced WTVs, we developed glycopolymer-engineered WTVs (G-WTVs) using a Halo-Tag protein (HTP) fusion technique and reversible addition-fragmentation chain transfer (RAFT) polymerization. In our study, G-WTVs with varying molecular weights of glycopolymers were constructed. Compared to unmodified tumor cells, all G-WTVs effectively induced the polarization of macrophages toward the M1 phenotype and promoted the secretion of pro-inflammatory cytokines. This enhanced immune response was attributed to the improved interactions between G-WTVs and the macrophages. Among the G-WTVs, the medium molecular weight variant demonstrated the most pronounced enhancement of antitumor immune responses. Notably, the administration of optimized G-WTVs effectively inhibited the growth of B16 melanoma in mice. Our findings provide a new approach to enhance the antitumor efficacy of WTVs via cell membrane glycopolymer engineering, offering a promising strategy for tumor immunotherapy.

Despite recent progress in cancer treatment, liver metastases persist as an unmet clinical need. Here, we show that arming liver and tumor-associated macrophages in vivo to co-express tumor antigens (TAs), IFNα, and IL-12 unleashes robust anti-tumor immune responses, leading to the regression of liver metastases. Mechanistically, in vivo armed macrophages expand tumor reactive CD8+ T cells, which acquire features of progenitor exhausted T cells and kill cancer cells independently of CD4+ T cell help. IFNα and IL-12 produced by armed macrophages reprogram antigen presenting cells and rewire cellular interactions, rescuing tumor reactive T cell functions. In vivo armed macrophages trigger anti-tumor immunity in distinct liver metastasis mouse models of colorectal cancer and melanoma, expressing either surrogate tumor antigens, naturally occurring neoantigens or tumor-associated antigens. Altogether, our findings support the translational potential of in vivo armed liver macrophages to expand and rejuvenate tumor reactive T cells for the treatment of liver metastases.

Immunotherapy has revolutionized cancer treatment and complements traditional therapies, including surgery, chemotherapy, radiation therapy, and targeted therapies. Immunotherapy redirects the patient's immune system against tumors via several immune-mediated approaches. Over the past few years, therapeutic immunization, which enable the patient's T cells to better recognize and kill tumors, have been increasingly tested in the clinic, with several approaches demonstrating treatment improvements. There has been a renewed interest in cancer vaccines due to advances in tumor antigen identification, immune response optimization, novel adjuvants, next-generation vaccine delivery platforms, and antigen designs. The COVID-19 pandemic accelerated progress in nucleic acid-based vaccine manufacturing, which spurred broader interest in mRNA or plasmid platforms. Enhanced DNA vaccine designs, including optimized leader sequences and RNA and codon optimizations, improved formulations, and delivery via adaptive electroporation using stereotactic intramuscular/intradermal methods have improved T cell responses to plasmid-delivered tumor antigens. Additionally, advancements for direct in vivo delivery of DNA-encoded monospecific/bispecific antibodies offer novel tumor-targeting strategies. This review summarizes the recent clinical data for therapeutic cancer vaccines utilizing the DNA platform, including vaccines targeting common tumor-associated and viral antigens and neoantigen vaccines using nucleic acid technologies. We also summarize preclinical data using DNA-launched monoclonal/bispecific antibodies, underscoring their potential as a novel cancer therapy tool.

As the seventh-leading contributor to global cancer-related deaths, esophageal cancer (EC) is one of the most challenging types of cancer. Despite advancements in conventional therapies, including surgery, chemotherapy, and radiotherapy, the five-year survival rate remains low, underscoring the need for the development of more efficacious treatment approaches. Immunotherapy has emerged as a promising treatment approach, offering new hope for EC patients. This review provides an in-depth examination of the latest immunotherapeutic strategies for EC, focusing on immune checkpoint inhibitors, adoptive cell therapy, cancer vaccines, and oncolytic virotherapy. We critically analyze the current clinical data to highlight the progress and pitfalls of each immunotherapeutic approach for EC. Additionally, we explore the potential for combination therapies, which could overcome the resistance often seen with monotherapies. Finally, we discuss the limitations of current treatments and outline key areas for future research to improve patient outcomes and survival.

The intricate interaction between skeletal muscle biomechanics, the tumor microenvironment, and immunotherapy constitutes a pivotal research focus oncology. This work provides a comprehensive review of methodologies for evaluating skeletal muscle biomechanics, including handheld dynamometry, advanced imaging techniques, electrical impedance myography, elastography, and single-fiber experiments to assess muscle quality and performance. Furthermore, it elucidates the mechanisms, applications, and limitations of various immunotherapy modalities, including immune checkpoint inhibitors, adoptive cell therapy, cancer vaccines, and combined chemoimmunotherapy, while examining their effects on skeletal muscle function and systemic immune responses. Key findings indicate that although immunotherapy is effective in augmenting antitumor immunity, it frequently induces muscle-related adverse effects such as weakness, fatigue, or damage, primarily mediated by cytokine release and immune activation. This work underscores the significance of immune niches within the tumor microenvironment in influencing treatment outcomes and proposes strategies to optimize therapy through personalized regimens and combinatorial approaches. This review highlights the need for further research on the formation of immune niches and interactions muscle-tumor. Our work is crucial for advancing the efficacy of immunotherapy, reducing adverse effects, and ultimately improving survival rates and quality of life of patients with cancer.

Glucose-regulated protein 94 (GRP94) overexpression plays a critical role in tumor cell survival across various cancers. Previously, we developed K101.1, a fully human antibody targeting cell surface GRP94, which effectively inhibits tumor angiogenesis in colorectal cancer (CRC). This study aims to identify K101.1's interaction site and further elucidate GRP94's role in tumor angiogenesis. In an HT29 CRC xenograft mouse model, K101.1 reduced tumor growth and angiogenesis by 30 % and 69 %, respectively, without inducing severe toxicity. Using hydrogen‑deuterium exchange mass spectrometry, we identified the binding site of K101.1 on GRP94, analyzing 225 peptides with 94.5 % sequence coverage and a redundancy score of 4.20. This revealed a linear epitope (Glu26-Ala34) as the specific binding site. The binding was further validated via enzyme-linked immunosorbent assay, and human umbilical vein endothelial cell tube formation assays using a synthetic epitope peptide corresponding to the identified epitope. Our findings suggest that this epitope is functionally involved in GRP94-mediated angiogenesis and is integral to its proangiogenic activity. By integrating epitope profiling with complementary experimental approaches, this study advances the understanding of GRP94's role in CRC angiogenesis and provides new insights for developing targeted cancer therapies and vaccines, offering promising avenues for CRC prevention and treatment.

Bacterial outer membrane vesicles (OMVs), naturally released by Gram-negative bacteria, are a type of lipid bilayer nanoparticles containing many components found within the parent bacterium. Despite OMVs were first considered mere by-products of bacterial growth, recent studies have shown them as a highly adaptable platform for tumor vaccine. Here, we first demonstrate the biogenesis of OMVs, then review the strong immunogenicity of OMVs as an immune adjuvant in tumor vaccine and its excellent vaccine delivery capability, and finally discuss OMVs' engineering potentials through summarizing recent scientific advancements in genetic engineering, chemical modification, and nanotechnology. We also point out the clinical trials and future challenges of OMV-based vaccine. Overall, this review offers valuable insights into cancer immunotherapy, providing a roadmap for leveraging OMVs as a versatile platform for next-generation cancer vaccines.

The primary objective of neoantigen vaccines is to elicit a robust anti-tumor immune response by generating neoantigen-specific T cells that can eradicate tumor cells. Despite substantial advancements in personalized neoantigen prediction using next-generation sequencing, machine learning, and mass spectrometry, challenges remain in efficiently expanding neoantigen-specific T cell populations in vivo. This challenge impedes the widespread clinical application of neoantigen vaccines. Nanovector-based neoantigen delivery systems have emerged as a promising solutions to this challenge. These nanovectors offer several advantages, such as enhanced stability, targeted intracellular delivery, sustained release, and improved antigen-presenting cell (APC) activation. Notably, they effectively deliver various neoantigen vaccine formulations (DC cell-based, synthetic long peptide (SLP)-based or DNA/mRNA-based) to APCs or T cells, thereby activating both CD4+ T and CD8+ T cells. This ultimately induces a specific anti-tumor immune response. This review focuses on recent innovations in neoantigen vaccine delivery vectors. We aim to identify optimal design parameters for vectors tailored to different neoantigen vaccine types, with an emphasis on enhancing the tumor microenvironment and stimulating the production of neoantigen-specific cytotoxic T cells. By maximizing the potential of these delivery systems, we aim to accelerate the clinical translation of neoantigen nanovaccines and advance cancer immunotherapy.

In recent years, several global phase III trials have shown that combinations of immune checkpoint inhibitors (ICIs) offer superior efficacy and survival compared to multi-kinase inhibitors, establishing them as the gold standard for treating patients with advanced hepatocellular carcinoma (HCC). This success has led to investigations into expanding the use of immunotherapy into various other settings and populations, including neoadjuvant and adjuvant therapies, patients with decompensated liver function and those awaiting liver transplantation. Despite its proven efficacy, a significant number of patients still develop resistance to immunotherapy, highlighting the need for innovative strategies to address this challenge. Approaches aimed at enhancing tumour immunogenicity, such as combining immunotherapy with transarterial chemoembolization or radiation therapies, show significant promise. Additionally, novel immunotherapeutics - such as triplet therapy, bispecific antibodies, adoptive T-cell therapy and cancer vaccines - are in early development for HCC. These agents have demonstrated potential for synergistic effects with existing ICIs, with initial studies yielding positive outcomes. In this review, we offer our future perspective on immunotherapy, emphasizing emerging indications, novel combination strategies and the development of new immunotherapeutic agents. Overall, the future of immunotherapy in HCC is brimming with extraordinary potential, set to transform the treatment landscape and redefine the possibilities for managing this challenging disease.