mRNA vaccines have emerged as a transformative platform in oncology, offering significant advantages in rapid development, flexibility, and safety over traditional modalities. However, their clinical translation faces challenges such as mRNA instability, inefficientin vivodelivery, and the immunosuppressive tumor microenvironment (TME). This review comprehensively outlines recent advancements in overcoming these hurdles. We discuss the molecular design of mRNA vaccines, including non-replicating and self-amplifying RNAs, and highlight breakthroughs in delivery strategies, particularly lipid nanoparticles (LNPs), that enhance stability and immunogenicity. Furthermore, we explore various administration routes and their impact on eliciting robust antitumor immunity. The review also covers the classification of antigens-viral, tumor-associated, and neoantigens-and the innovative use of mRNA to encode immunomodulators to reprogram the TME. Finally, we address key considerations for clinical translation, including manufacturing, stability, safety, and combination strategies with immunotherapies. By synthesizing these developments, this review underscores the potential of mRNA vaccines to realize personalized cancer immunotherapy and outlines future directions for the field.

In silico technologies are increasingly shaping vaccine development, supporting the field beyond empirical discovery toward rational, data-driven design. Contemporary computational pipelines enable rapid antigen screening, high-precision epitope-MHC binding prediction, structural modeling, and immune response simulations. These approaches are accelerating vaccine discovery not only for infectious diseases but also in oncology, where neoantigen prediction underpins personalized cancer immunotherapy. This review explores recent advances in computational pipelines for epitope-based vaccine design, covering antigen discovery; B- and T-cell epitope mapping; safety and specificity assessment; vaccine construct assembly with adjuvants and linkers; structural modeling; and immune-response simulations that predict efficacy in specific disease contexts using advanced platforms. It showcases applications in infectious diseases, including SARS-CoV-2, tuberculosis, and influenza, and poxivirus infections, as well as in cancer immunotherapy. It is based on literature obtained through searches utilizing PubMed, Scopus, and Web of Science databases covering publications up to 2025, using combinations of keywords such as epitope-based vaccines, reverse vaccinology, immunoinformatics, and immune system simulation. In silico approaches offer a transformative advantage to vaccine research by delivering speed, cost-efficiency, and enhanced precision. Yet the predictive power of current computational pipelines is still constrained by algorithmic limitations and by their incomplete integration of immune-regulatory processes. Progress in artificial intelligence, multi-omics integration, and formal recognition of digital evidence by regulatory agencies will be crucial for narrowing the gap between computational predictions and experimental validation. Ultimately, combining predictive immunoinformatics with advanced immune simulations and rigorous verification could help establish in silico methodologies as a cornerstone of next-generation vaccine development.

Mucosal-associated invariant T (MAIT) cells are unique unconventional T cells with diverse roles in immunity, yet how their context informs their function is not well known. This contextual regulation is particularly relevant in cancer, where MAIT cells have an enigmatic role. We performed a systematic review and meta-analysis to identify MAIT cell transcriptomic signatures under different environmental conditions. We identified four bulk-RNA-sequencing studies that compared multiple activation stimuli. We found a stimulus-specific transcriptional signature for immune checkpoint genes, that we confirmed in a single-cell RNA-sequencing dataset. We used flow cytometry to examine in vitro human MAIT cells across four activation stimuli and confirmed that stimulus drives unique checkpoint signatures upon MAIT activation for Lag3, PD-L1, PD-1, NKG2A and Tigit. Strikingly, PD-L1 was more highly induced in vitro than PD-1 in MAIT cells up to 72 hours. Our data suggest that human MAIT cell regulation is context-dependent. These findings have the potential to critically inform efforts targeting MAIT cells for cancer immunotherapy.

Adoptive T-cell therapy has emerged as a transformative modality in cancer immunotherapy, building upon foundational principles established in allogeneic hematopoietic stem cell transplantation. In this setting, while donor T cells mediate curative graft-versus-leukemia and graft-versus-infection effects, their alloreactivity poses significant risks. Gene transfer strategies-such as suicide gene insertion-have enabled the safer use of donor lymphocytes by allowing the selective elimination of T cells in case of adverse events. With this initial gene therapy approach, several lessons on the function, persistence, safety, and efficacy of engineered T cells were learned. More recently, advances in genome editing technologies have enabled precise manipulation of T-cell genomes and function, including disruption of endogenous T-cell receptors (TCRs) and insertion of tumor-specific receptors, such as chimeric antigen receptors and tumor-specific TCRs. Integration of T-cell manufacturing protocols optimized for persistence and resistance to immune suppression-largely facilitated by the possibility to simultaneously edit multiple genes (multiplex genome editing) in the same cells-has positioned engineered T cells as programmable and persistent therapeutics. Here, we briefly review key milestones, challenges, and innovations in T-cell gene engineering, from allogeneic hematopoietic stem cell transplantation to next-generation TCR-edited immunotherapies.

Immunotherapy has revolutionized the landscape of cancer treatment, yet its efficacy is often limited by drug resistance, the immunosuppressive tumor microenvironment (TME), and the "undruggable" nature of key immunoregulatory proteins. Targeted protein degradation (TPD) technology, which harnesses cellular degradation machinery to eliminate disease-associated proteins, is emerging as a transformative strategy in the field of tumor immunotherapy. This review systematically summarizes recent advances in various TPD strategies-based on both the ubiquitin-proteasome system (UPS) and the lysosomal pathway, such as proteolysis-targeting chimera (PROTAC), molecular glues, lysosome-targeting chimera (LYTAC), and antibody-based PROTAC (AbTAC)-within the context of cancer immunotherapy. We emphasize how TPD molecules can directly degrade key target proteins, including immune checkpoints, to alleviate immunosuppression, as well as clear critical immunomodulatory factors within the TME, thereby synergistically reversing immunosuppression and enhancing antitumor immunity. Furthermore, this article discusses the rational design, preclinical validation, and clinical translation trends of TPD-based immunotherapeutic agents. Despite encouraging progress, challenges such as tissue selectivity, off-target effects, and delivery efficiency remain to be addressed. Finally, we envision future directions for advancing the application of TPD technology in cancer immunotherapy.

Cancer immunotherapy has advanced through immune checkpoint inhibitors and T cell therapies, yet challenges persist in overcoming immune evasion. Neoantigen-based vaccines have shown promise, particularly in tumors with high tumor mutation burden. However, logistical barriers and tumor heterogeneity limit their scalability. Shared oncogenic driver mutations (e.g., KRAS, EGFR, IDH) offer a stable and broadly applicable alternative. Clinical trials demonstrate their immunogenicity and potential in minimal residual disease settings. Advances in vaccine delivery and immune modulation, including adjuvants and cytokine-based therapies, may further enhance efficacy. This review explores the evolution of oncogene-directed vaccines, their clinical impact, and future strategies to optimize their therapeutic potential.

Humans are metaorganisms, composed of both host (human) cells and a roughly equal number of commensal microorganisms-collectively known as the microbiome-residing primarily at epithelial barrier surfaces. This review considers human cancer as a disease of the metaorganism, to which the microbiome contributes by influencing genome stability, tissue organization, inflammation, immunity, tumor initiation and promotion, metastasis formation, and therapeutic response. We summarize evidence demonstrating that machine learning models trained on patients' microbiome features moderately predict clinical response to immunotherapy and the development of immune-related adverse events. We review results from single-arm and randomized clinical trials wherein fecal microbiome transplantation from therapy-responsive patients or healthy donors, when combined with therapy targeting programmed cell death 1 (PD-1), improved outcomes in PD-1-refractory patients or served as an effective first-line intervention. We conclude by highlighting the emerging opportunities and ongoing challenges in leveraging the microbiome to enhance the efficacy and safety of cancer immunotherapy.

BackgroundBispecific antibodies that redirect T cells or NK cells to tumors have demonstrated substantial therapeutic efficacy, but their broader application is often constrained by immune-related toxicities, limited effector cell availability, and suboptimal access to tumor sites. These challenges have prompted efforts to identify alternative effector cell types that are more abundant in circulation, readily accessible, and capable of cytotoxic activity in the tumor microenvironment. Neutrophils, which constitute the most prevalent circulating leukocyte population, represent a promising yet underutilized target for immune cell engager design. However, efforts to exploit neutrophil-mediated tumor killing through CD89 (FcαRI) have been limited by the inherent drawbacks of IgA-based formats, including poor stability, short serum half-life, and reduced developability.ResultsTo address these challenges, we established an engineered bispecific antibody platform that incorporates CD89 engagement into an IgG1 scaffold. This design enables neutrophil redirection while preserving the favorable pharmacokinetic and manufacturing profiles of IgG-based therapeutics. The resulting bispecific architecture allows for programmable neutrophil engagement alongside tumor antigen recognition, offering a clinically viable strategy for innate immune activation. Among the bispecific designs evaluated, ZT-8, a humanized CD89 × HER2 bispecific antibody, demonstrated potent neutrophil-mediated cytotoxicity against tumor cells even in the absence of cytokine priming, suggesting a distinct activation mechanism that operates within the tumor microenvironment. Compared to IgA-based antibodies, ZT-8 exhibited superior immune effector engagement, enhanced tumoricidal activity, and substantially prolonged in vivo half-life through FcRn-mediated recycling.ConclusionThese findings define IgG-based CD89 bispecifics as a next-generation neutrophil engager platform and exemplify how antibody engineering and synthetic immunology can be leveraged to expand the effector landscape of bispecific immunotherapies.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13036-025-00580-2.

CD73, a membrane-bound ecto-5'-nucleotidase, catalyzes the extracellular conversion of adenosine monophosphate into immunosuppressive adenosine. Functioning as an emerging immune checkpoint, CD73 is frequently upregulated across numerous tumor types, contributing to the accumulation of adenosine within the tumor microenvironment and promoting immune evasion. Intensive efforts have led to the discovery of diverse CD73 inhibitors, which show strong potential in cancer immunotherapy. To date, around eighteen candidates targeting CD73 have entered clinical evaluation, many exhibiting encouraging efficacy in combination regimens for solid tumors. This review provides an overview of the biological functions of CD73 in tumor-induced immunosuppression and highlights the medicinal chemistry strategies employed in the development of small-molecule CD73 inhibitors since 2018. Additionally, the challenges in drug design and future directions are also discussed to enhance the clinical applicability of CD73-targeted therapies in cancer treatment. We believe that this review will offer valuable insights to guide the rational design of next-generation CD73 inhibitors for cancer immunotherapy.

Microbiota and Cancer Immunotherapy: Mechanisms, Clinical Implications, and Precision Therapeutics.

The discovery of ferroptosis as a novel mechanism of cell death has opened the door to a new scenario in which it could be used to support current cancer therapy, particularly in cases of relapse. Several compounds have been developed aimed to inhibit or induce ferroptosis in cancer cells by acting on different signaling pathways caable of activating or repressing, respectively, this cell death mechanism. This review shows how treatmenting cancer cells with ferroptosis inducers results in improved efficacy of immunotherapy. Indeed, the advantage of affecting ferroptosis lies in the capacity of compounds to improve immune system compartments. The involvement of ferroptosis in cancer treatment is now emerging, demonstrating the high translational potential of this approach capable of carrying out an immune response against tumors, dendritic cells (DC), regulatory T cells (Treg), Natural Killer cells (NK) and tumor-associated macrophages (TAM) exert an interesting role. Some immune check-point inhibitors (ICIs) have been approved as cancer immunotherapy, because they target cytotoxic T lymphocyte-associated antigen 4 (CTLA4), programmed cell death protein 1 (PD-1) and its ligand PD-L1. For this reason, promising results have been achieved by combining ferroptosis inducers with ICIs. At the same time, combining Chimeric Antigen Receptor (CAR) T-cell therapy with ferroptosis inducers shows promising anti-tumor activity, particularly in solid tumors. This approach demonstrates how the modulation of ferroptosis may improve the efficacy of CAR T-cells treatment by promoting tumor cell death and enhancing immunogenicity. In conclusion the development of clinical trials aimed at testing the efficacy of ferroptosis induction in combination with current cancer therapy will be the definitive proof of the valid opportunity provided by this therapeutic approach.

A matrix metalloproteinase-responsive hydrogel delivers dendritic cell-targeting nanoparticles for sustained antitumor immunity.

BackgroundT-cell exhaustion induced by the tumor microenvironment is an important factor in posing a major challenge to effective cancer immunotherapy. Immune checkpoint inhibitors aim to reverse T-cell exhaustion. However, the effectiveness of immune checkpoint inhibitors is often limited due to their off-target effects and single targets. Herein, we attempt to identify molecular targets that can regulate the expression of multiple immune checkpoints to reverse T-cell exhaustion.MethodsNSG mice with xenotransplantation of human bladder cancer cells were used to investigate the function of nuclear paraspeckle assembly transcript 1 (NEAT1) in T-cell exhaustion. Chromatin isolation by RNA purification, chromatin immunoprecipitation, and luciferase assays was employed to investigate the molecular mechanisms by which NEAT1 regulates expression of target genes.ResultsNEAT1, a bladder cancer-related long non-coding RNA (lncRNA), promotes lactate production in tumor cells by binding to the lactate dehydrogenase A gene. This lactate production subsequently inhibits NEAT1 expression in CD8+T cells. Furthermore, NEAT1 in CD8+T cells plays a crucial role in modulating the immune response of CD8+T cells against tumor cells. Our findings indicate that NEAT1 regulates the expression of multiple immune checkpoint genes by directly binding to them and inhibiting transcription through the alteration of histone lactylation near transcriptional start sites, which affects RNA polymerase II recruitment.ConclusionslncRNA NEAT1 serves as a modulator of the antitumor response of CD8+T cells in the bladder tumor microenvironment and may represent a therapeutic target for reversing T-cell exhaustion.

Opportunities and challenges in applying microbiota to clinical cancer immunotherapy.

Structure characterization of a polysaccharide isolated from sugarcane leaves and its macrophage polarization activity and beneficial effects for cisplatin treatment of lung cancer.

Multimodal chitosan-based materials for combination immunotherapy in cancers: Structural engineering, immune regulatory mechanisms and synergistic therapeutic applications.

CRISPR-Cas9: a prominent genome editing tool in the management of inherited blood disorders and hematological malignancies.

T cell-macrophage crosstalk in GVHD and cancer immunotherapy

A dual PROTAC nanocarrier amplifies DNA damage and STING activation for cancer immunotherapy.

From innate power to intelligent design: The evolution of NK cell-based cancer immunotherapy.