Bioorthogonal pre-targeting alleviate the limitations of traditional nanomedicines in passive and active targeting delivery. However, the high selectivity of bioorthogonal pre-targeting depends on the high expression level of antigens in lesion sites, and there are very limited targets with sufficient overexpression. Herein, we propose a tumor heterogeneity-independent antigen-responsive nanocarrier utilizing bioorthogonal pre-targeting and click-activated self-immolative polymers for stimulus signal conversion and amplification. This approach comprises a tetrazine (Tz) conjugated with trastuzumab (T-Tz), and a bioorthogonally activatable nanocarrier CONP which self-assembled by isocyanide and polyethylene glycol-modified poly (thiocarbamate) (NC-PTC-PEG) and hydrogen sulfide (H2S)-responsive self-immolative polymers. In practice, T-Tz is first injected to actively pretarget HER2-positive tumor cells and followed by the second injection of nanocarrier CONP. The NC-PTC-PEG in CONP undergoes a click reaction with Tz to generate H2S, thereby achieving the transformation from antigen signal to H2S signal. Finally, NO2-PTC-PEG responds to H2S stimulation and undergoes a head-to-tail depolymerization process similar to dominoes to produce a large amount of H2S, further amplifying the stimulus signal. This bioorthogonal pre-targeting combine with click-activated self-immolative polymers is anticipated to enhance the effectiveness of existing pre-targeting strategies for tumor imaging and therapy, with the potential to overcome challenges posed by tumor heterogeneity.

A theranostic nanomedicine for CD3+ bispecific antibodies targeting glycoprotein-100 (GP-100) was tested in vivo using two radiation sessions. CT-imageable nanoparticles composed of hyaluronate-alginate and designed to release their contents upon radiation exposure were evaluated in a mouse model of B16-melanoma model in the left hind leg with pulmonary metastases.

In session 1, IFN-γ was encapsulated during the Fe polymerization of hyaluronate-alginate nanoparticles. Nine hours after the intravenous injection of 1 × 1010 IFN-γ nanoparticles, enough to observe dose escalation of either 10 or 20 Gy was administered using 140 keV-X-ray to the primary and metastatic tumors. In session 2, tebentafusp was encapsulated using the same method as in session 1. Seventy-two hours after the intravenous injection of 1 × 1010 tebentafusp-loaded nanoparticles, radiation was administered under conditions identical to those in session 1.

In session 1, IFN-γ-loaded nanoparticles selectively accumulated in the primary tumor and pulmonary metastasis by passing through the coarse endothelium of tumor vasculature, which could be visualized using CT. IFN-γ nanoparticles continuously released IFN-γ, facilitating the formation of the HLA-A*02:01-GP100-complex. In session 2, the tebentafusp-loaded nanoparticles continuously released tebentafusp, leading to the formation of an immunological synapse consisting of HLA-A*02:01-GP100, tebentafusp, and CD3 on T cells. CD3+ T cells release perforin and granzymes, resulting in the cytolysis of the primary tumor and pulmonary metastasis. This effect was synergistic with that of radiation, resulting in Enhancement Factor (EF) more than 1.

Theranostic nanomedicine demonstrated potential as a dual therapeutic and diagnostic strategy for targeting tumors and metastases, with synergistic effects observed when combined with radiation.

In recent years, the USFDA-approved drug molecules are being frequently analyzed to provide perspectives and strategies for novel therapeutic discovery and development. Some of the remarkable analyses include physicochemical properties of drugs relevant to oral bioavailability, frequent presence of drug relevant-structural motifs, natural products as sources of new drugs, and synthetic approaches to new drugs. In this review article, for the first time, we present a structure-function analysis of human topoisomerase II (hTopo II) inhibitors those are currently clinically used or under clinical trials for anticancer treatment. The case studies and a critical molecular medicinal insight for their therapeutic development have been presented. The review illustrates various key aspects: the hTopo II inhibitors' molecular modulations, common pharmacophores, interactions at molecular level crucial for inhibition of enzyme at its various stages of catalytic function, and network polypharmacology of Topo II with different targets. Numerous toxicophore motifs have been identified, which provide important alerts while designing and discovering novel therapeutic agents. A range of innovative approaches including property-focused strategies, ADCs, and Click Activated Protodrugs Against Cancer (CAPAC) that have addressed challenges faced in the hTopo II-based therapeutic development have been discussed. The analysis with perspectives represents a valuable educational and research resource that will encourage hTopo II-inhibition and its network polypharmacology based drug discovery studies.

Ovarian cancer is one of the most lethal gynaecologic cancers in China. Although platinum-based chemotherapy, PARP inhibitors and bevacizumab have prolonged long term survival and increased the overall response rate for platinum-sensitive ovarian cancer (PSOC), the treatment options for platinum-resistant ovarian cancer (PROC) are still limited. Antibody-drug conjugates (ADCs) represent a novel form of precision medicine, covalently linking specific monoclonal antibodies with potent cytotoxic payloads. Since mirvetuximab soravtansine (MIRV) received approval by the US Food and Drug Administration (FDA) as the first ADC for PROC in 2022, the development of novel ADCs for various targets in PROC has accelerated. In this review, we summarise the recent evidence and future prospects of ADCs targeting Folate Receptor alpha (FRα), mesothelin, cadherin-6, NaPi2b, human epidermal growth factor receptor 2 (HER2), dipeptidase 3 (DPEP3), B7-H4 (VTCN1), claudin-6 (CLDN6) and trophoblast antigen protein 2 (TROP2), in order to enhance our understanding of the clinical applications of ADCs and offer new insights for clinical practice and further research.

Monoclonal antibodies (mAbs) and antibody fragments have revolutionized medicine as highly specific binding agents and inhibitors. At the same time, several types of nanomaterials, including liposomes, lipid nanoparticles (NPs), polymersomes, metal and metal oxide NPs, and protein nanostructures, are increasingly utilized and explored for therapeutic potential due to their versatility, chemical and physical properties, and tunability. However, nanomaterials alone often lack specificity, leading to relatively low efficacy and/or high toxicity. To address this problem, a rapidly emerging area is antibody-nanomaterial conjugates (ANCs), which combine the precise targeting specificity of antibodies with the effector functionality of the nanomaterial. In this review, we give a brief introduction to mAbs and major conjugation techniques, describe major classes of nanomaterials being studied for therapeutic potential, and review the literature on ANCs of each class. Special focus is given to emerging applications including ANCs addressing the blood-brain barrier, ANCs delivering nucleic acids, and light-activated ANCs. While many disease targets are related to cancer, ANCs are also under development to address autoimmune, neurological, and infectious diseases. While important challenges remain, ANCs are poised to become a next-generation therapeutic technology.

Antibody-drug conjugates (ADCs) are a rapidly evolving class of antitumor drugs and have already revolutionized the treatment strategy of many hematologic and solid cancers. So far, trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) are the four ADCs that have been approved by US food and drug administration (FDA) in treatment of breast cancer, and SKB264 has been approved by Chinese national medical products administration (NMPA). Many ADCs for treatment of breast cancer are currently being tested in late-phase clinical trials, with several encouraging results achieved recently. However, major issues arise during the use of ADCs, including emergence of acquired resistance, occurrence of treated-related toxicities, and identification of biomarkers of response and resistance. ADCs are being increasingly tested in combination with other agents, and novel next-generation ADC development is progressing rapidly. A better understanding of the design and development of ADCs will promote ADC development for cancer treatment. In this review, we aim to provide a broad overview of the design and the recent advances of ADCs in breast cancer. We also propose several notable future directions of ADCs in treatment of breast cancer.

Targeted drug delivery systems effectively solve the problem of off-target toxicity of chemotherapeutic drugs by combining chemotherapeutic drugs with antibodies or peptides, thereby promoting drug targeting to the tumor site and bringing further hope for cancer treatment. The development of stimulus-responsive smart linkage technologies has led to the emergence of drug conjugates. Linkage technologies play a crucial role in the design, synthesis, and in vivo circulation of drug conjugates, as they determine the release of cytotoxic drugs from the conjugates and their subsequent therapeutic efficacy. This article reviews some of the smart linkage strategies used in designing drug conjugates, with a focus on the tumor microenvironment and exogenous stimuli as conditions influencing controlled drug release. This review introduces linker classifications and cleavage mechanisms, discusses modular linkers that promote the efficient synthesis of conjugates, and discusses the differences between linkage strategies. Furthermore, this article focuses on the implementation of self-assembly in drug conjugates, which is currently of great interest. Related concepts are introduced and relevant examples of their applications are provided. Furthermore, a comprehensive discourse is presented on the challenges that may arise in the research and clinical implementation of diverse linkage strategies, along with the associated enhancement measures. Finally, the factors that should be considered when designing linkage strategies for drug conjugates are summarized, offering strategies and ideas for scientists involved in drug conjugate research. It is particularly noteworthy that appropriate linkage strategies allow for the intracellular release of drugs after internalization of the conjugates, thereby maximizing their tumor cell-killing effect.

The antibody, linker, and payload moieties all play a significant role in giving the ADC its unique therapeutic potential. The antibody subclass employed in ADCs is determined based on relative individual receptor affinities and pharmacokinetics. Meanwhile, the linker used in an ADC can either be cleavable or non-cleavable. ADC therapy comprises antibody-dependent mechanisms in addition to the direct cytotoxic effects of the payload. These include antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, as well as the "bystander effect", which refers to the diffusion of a portion of the cytotoxic molecules out of the target cell, exerting its cytotoxic effect on the adjacent cells. Target antigens of ADCs are expected to be expressed on the membranes of the cancer cells facing the external matrix, although new approaches utilize antigens regarding tumor-associated cells, the tumor microenvironment, or the tumor vasculature. These target antigens of ADCs not only determine the efficacy of these agents but also impact the off-targets and related adverse effects. The majority of ADC-related toxicities are associated with off-targets. The proposed mechanisms of ADC resistance include disrupted intracellular drug trafficking, dysfunctional lysosomal processing, and the efflux of the cytotoxic molecule via ATP-binding cassette (ABC) transporters. The latter mechanism is especially prominent for multi-drug-resistant tumors. An important limitation of ADCs is the penetration of the conjugate into the tumor microenvironment and their delivery to target cancer cells. Cancerous tissues' vascular profile and the steric "binding site barrier" formed around the peripheral vessels of tumors stand as potential challenges of ADC therapy for solid tumors. As research efforts focus on reducing toxicities, overcoming resistance, and improving pharmacokinetics, ADC options for cancer therapy are expected to continue to diversify, including standalone approaches and combination therapies.

One of the major limitations of cancer therapy is the emergence of drug resistance. This review amis to provide a focused analysis of the multifactorial mechanisms underlying therapy resistance,with an emphasis on actionable insights for developing novel therapeutic strategies. It concisely outlines key factors contributing to therapy resistance, including drug delivery barriers, cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), cancer heterogeneity, tumor microenvironment (TME), genetic mutations, and alterlations in gene expression. Additionally, we explore how tumors evade targeted therapies through pathway-specific mechanisms that restore disrupted signaling pathways. The review critically evaluates innovative strategies designed to sensitize resistant tumor cells, such as targeted protein dedgradation, antibody-drug conjugates, structure-based drug design, allosteric drugs, multitarget drugs, nanomedicine and others We also highlight the importance of understanding the pharmacological actions of these agents and their integration into treatment regimens. By synthesizing current knowledge and identifying gaps in our understanding, this review aims to guide future research and improve patient outcomes in cancer therapy.

B-cell non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy, capable of invading the brain, meninges, and nerve roots of the brain and spine, leading to high lethality. Herein, we designed and developed novel nanostructures for the first time by biofunctionalizing chitosan with two specific antibodies (i.e., anti-CD20, anti-CD19, and bispecific biopolymer-antibody) against NHL, conjugated with fluorescent nanoprobes. These bioengineered immunoconjugates formed water-dispersed hybrid colloidal nanostructures consisting of a photoluminescent ZnS-based quantum dots core and an antibody-modified chitosan macromolecular shell. The aim was to apply them simultaneously for the diagnosis, bioimaging, and immunotherapy of NHL cancers. The chitosan backbone was covalently functionalized with anti-CD20, anti-CD19, and both antibodies, resulting in biocompatible immunoconjugates through an eco-friendly aqueous process. Importantly, these biopolymer-antibody nanoimmunoconjugates exhibited bioaffinity for both antigenic membrane receptors, CD19 and CD20, which are overexpressed by NHL cancer cells. They served as fluorescent nanoprobes for bioimaging and specifically killing NHL cells, while remarkably preserving nonmalignant cells. Furthermore, biopsies from tumor tissues of a patient with NHL confirmed the effective anticancer potential for clinical applications in fluorescent ex vivo immunohistochemistry diagnosis of NHL cancers. It can be envisioned that these dual-antibody-modified biopolymer nanoarchitectures offer a new realm to be exploited in immunotheranostic applications for fighting cancer.

Antibody-drug conjugates (ADCs) combine the specificity of monoclonal antibodies with the potency of highly cytotoxic drugs and are known as panaceas, completely changing the treatment paradigm for solid tumors. Compared with other anti-cancer drugs, do they have better efficacy and lower toxicity risks? It is necessary to summarize and analyze the published clinical research data in this area to provide additional evidence-based evidence for clinical practice.

To comprehensively assess and overview the efficacy and safety of antibody-drug conjugates for the treatment of solid tumors.

An umbrella review of systematic reviews and meta-analyses.

Systematic search of eight electronic databases and one registration platform including Embase, PubMed, Cochrane Database of Systematic Reviews (CDSR), Web of Science (WoS), China National Knowledge Infrastructure (CNKI), Chinese BioMedical Literature Database (CBM), Wan Fang Data, China Science and Technology Journal Database (VIP) and international prospective register of systematic reviews (PROSPERO) on Aug 1, 2024, to identify relevant systematic reviews or meta-analyses. Three authors completed research screening and data extraction independently. AMSTAR 2 was used to evaluate the methodological quality of the included studies and the Grading of Recommendations Assessment, Development and Evaluation Working Group (GRADE) was performed to evaluate the quality of the evidence. We examined progression-free survival (PFS), overall survival (OS), objective response rate (ORR) as efficacy endpoints, and the incidence of adverse events (AEs) as safety profiles.

A total of 16 eligible publications, including 32 clinical studies, were included in the umbrella review. The methodological quality of the included study was poor, with 2 articles of moderate-quality (12.5%), 5 articles of low quality (31.25%), and 9 articles of critically low quality (56.25%). Only one third of the evidence was of high quality. Within the included studies, breast cancer accounted for four-fifths, 2 studies were gastric cancer, and 1 study was a solid tumor. The overall results showed that ADCs significantly increased PFS and OS in patients with solid tumors, and the risk of toxicity was within an acceptable range. ado-Trastuzumab emtansine (T-DM1) and Trastuzumab deruxtecan (T-Dxd) treatment of human epidermal growth factor receptor 2(HER2) low/positive advanced metastatic breast cancer significantly prolonged PFS and OS, but the ORR showed a significant advantage. Compared with the chemotherapy group, T-Dxd significantly prolonged OS and PFS in gastric cancer patients, while T-DM1 did not. In other cancer types (ovarian cancer, renal cell carcinoma, and malignant pleural mesothelioma), ADCs tended to extend overall survival or progression-free survival compared with controls, but the difference was not statistically significant.

Based on the available evidence, in breast cancer, ADCs were proved to with significant improvements in prolonging survival time and demonstrates a tolerable safety profile. Meanwhile, ADCs were proved to have enormous potential for the treatment of solid tumors. However, well-designed, multi-center RCTs need to further identify its potential in various solid tumors.

PROSPERO CRD 42,024,564,517.

Acute myeloid leukemia (AML) is a deadly form of leukemia, and its treatment often leaves patients immunocompromised, making them vulnerable to fungal infections. Radioimmunotherapy (RIT) is explored for both AML and fungal infections. This study compares the radiobiological effects of alpha emitter Actinium-225 (225Ac) and beta emitter Lutetium-177 (177Lu)-labeled antibodies on AML and Cryptococcus neoformans cells.

AML OCI-AML3 and C. neoformans Cap-67 cells were treated with anti-(1-3)-beta-glucan antibody 400-2 and anti-CD33 antibody HuM-195, conjugated to DOTA and radiolabeled with 225Ac or 177Lu. Clonogenic survival, γH2A/X staining, and micronuclei assays were conducted. Antibody internalization was assessed by flow cytometry.

Both 225Ac- and 177Lu-enabled RIT resulted in decreased clonogenic survival in Cap-67 and OCI-AML3 cells, with Cap-67 recovering more rapidly. DNA double-strand breaks and micronuclei formation revealed DNA damage, with fewer micronuclei in OCI-AML3 cells due to radiation destruction. HuM-195 antibody internalized into OCI-AML3 cells, whereas 400-2 did not internalize into Cap-67 cells.

While both cell lines showed similar responses to 225Ac- and 177Lu-enabled RIT, variations were observed based on cellular structure, doubling times and DNA repair mechanisms. This study offers insights for future in vivo research on fungal infections in cancer setting.

Cancer immunotherapy is currently a very promising therapeutic strategy for treating tumors. However, its effectiveness is restricted by insufficient antigenicity and an immunosuppressive tumor microenvironment (ITME). Pyroptosis, a unique form of programmed cell death (PCD), causes cells to swell and rupture, releasing pro-inflammatory factors that can enhance immunogenicity and remodel the ITME. Nanomaterials, with their distinct advantages and different techniques, are increasingly popular, and nanomaterial-based delivery systems demonstrate significant potential to potentiate, enable, and augment pyroptosis. This review summarizes and discusses the emerging field of nanomaterials-induced pyroptosis, focusing on the mechanisms of nanomaterials-induced pyroptosis pathways and strategies to activate or enhance specific pyroptosis. Additionally, we provide perspectives on the development of this field, aiming to accelerate its further clinical transition.

Antibody-drug conjugates (ADCs) have advanced as a mainstay among the most promising cancer therapeutics, offering enhanced antigen targeting and encompassing wide diversity in their linker and payload components. Small-molecule inhibitors of tubulin polymerization have found success as payloads in FDA approved ADCs and represent further promise in next-generation, pre-clinical and developmental ADCs. Unique dual-mechanism payloads (previously designed and synthesized in our laboratories) function as both potent antiproliferative agents and promising vascular disrupting agents capable of imparting selective and effective damage to tumor-associated microvessels. These payloads have been incorporated into a variety of drug-linker constructs utilizing the clinically relevant cathepsin B cleavable Val-Cit dipeptide linker, employed within several FDA approved ADCs, along with other non-cleavable constructs. Various synthetic strategies were evaluated to prepare these drug-linker constructs. Aniline-based payloads were incorporated utilizing the Val-Cit dipeptide linker similar to FDA approved ADCs such as Adcetris® (brentuximab vedotin). An additional self-immolative group, previously described in the literature for related model systems, was employed to tether the phenolic payloads. A variety of drug-linker constructs (with each bearing a unique dual mechanism payload) were synthesized and evaluated biologically for their enzyme-mediated release of payload and inhibition of tubulin polymerization. Following deactivation of the highly electrophilic maleimido terminus as its corresponding N-acetyl cysteine (NAC) derivative, the most promising construct (NAC-4) demonstrated approximately 90% release of an aniline-functionalized payload (1) upon treatment with cathepsins B or L over 90 minutes. Building on these promising results, future studies will examine the conjugation of drug-linker construct 4 to selected antibodies and engineered proteins and evaluate the biological activity of the resultant antibody-drug conjugates (ADCs).

Design and development of efficient drug delivery technologies that impart site-specificity is the need of the hour for the effective treatment of lung cancer. The emergence of materials science and nanotechnology partially helped drug delivery scientists to achieve this objective. Various stimuli-responsive materials that undergo degradation at the pathological tumor microenvironment (TME) have been developed and explored for drug delivery applications using nanotechnological approaches. Nanoparticles (NPs), owing to their small size and high surface area to volume ratio, demonstrated enhanced cellular internalization, permeation, and retention at the tumor site. Such passive accumulation of stimuli-responsive materials helped to achieve spatiotemporally controlled and targeted drug delivery within the tumors. In this review, we discussed various stimuli-physical (interstitial pressure, temperature, and stiffness), chemical (pH, hypoxia, oxidative stress, and redox state), and biological (receptor expression, efflux transporters, immune cells, and their receptors or ligands)-that are characteristic to the TME. We mentioned an array of biomaterials-based nanoparticulate delivery systems that respond to these stimuli and control drug release at the TME. Further, we discussed nanoparticle-based combinatorial drug delivery strategies. Finally, we presented our perspectives on challenges related to scale-up, clinical translation, and regulatory approvals.

Cyclin-dependent kinases, CDK7 and CDK9 play critical roles in cancer by regulating transcriptional processes essential for cell proliferation and survival. Their dysregulation leads to aberrant gene expression, promoting oncogenic pathways and contributing to tumor growth and progression. This study aimed to identify a new chemotype for CDK7/9 inhibitors using a structure-based virtual screening approach. Our research led to the discovery of mitoxantrone as an inhibitor of CDK7/H and CDK9/T1 from a library of FDA-approved small molecule drugs. Mitoxantrone, a chemotherapy agent used to treat acute nonlymphocytic leukemia, works by disrupting DNA synthesis and repair, thus inhibiting cancer cell growth. The study found that mitoxantrone effectively inhibits both CDK7/H and CDK9/T1 with IC50 values of 0.675 µM and 5.15 µM, respectively, while showing no inhibition of CDK2/E1 (IC50 > 100 µM) in in-vitro ADP-Glo kinase assay. It binds to the ATP pocket of CDK7 and CDK9, forming crucial H-bonds with MET 94 and CYS 106, respectively. It achieves dock scores of - 12.93 and - 12.59 kcal/mol, and MMGBSA binding energies of - 82.87 and - 81.59 kcal/mol, respectively. Molecular dynamics simulations over 100 ns confirmed stable interactions with MET 94 and CYS 106 in the hinge region of CDK7 and CDK9. The active site sequence alignment helped to understand the differential activity of mitoxantrone for CDK7, 9 and 2 inhibitions. The findings of the paper reveal a novel mechanism of mitoxantrone action that may contribute to its anticancer efficacy.

Natural compound-derived chemotherapies remain central to cancer treatment, however, they often cause off-target side effects that negatively impact patients' quality of life. In contrast, antibody-drug conjugates (ADCs) combine cytotoxic payloads with antibodies to specifically target cancer cells. Most approved and clinically investigated ADCs utilize naturally derived payloads, while those with conventional synthetic molecular payloads remain limited. This review focuses on approved ADCs that enhance the efficacy of naturally derived payloads by linking them with antibodies. We provide an overview of the core components of ADCs, their working mechanisms, and FDA-approved ADCs featuring naturally derived payloads, such as calicheamicin, camptothecin, dolastatin 10, maytansine, pyrrolbenzodiazepine (PBD), and the immunotoxin Pseudomonas exotoxin A. This review also explores recent clinical advancements aimed at broadening the therapeutic potential of ADCs, their applicability in treating heterogeneously composed tumors and their potential use beyond oncology. Additionally, this review highlights naturally derived payloads that are currently being clinically investigated but have not yet received approval. By summarizing the current landscape, this review provides insights into promising avenues for exploration and contributes to the refinement of treatment protocols for improved patient outcomes.

Liposomal nanomedicines have emerged as a pivotal approach for the treatment of various diseases, notably cancer and infectious diseases. This manuscript provides an in-depth review of recent advancements in liposomal formulations, highlighting their composition, targeted delivery strategies, and mechanisms of action. We explore the evolution of liposomal products currently in clinical trials, emphasizing their potential in addressing diverse medical challenges. The integration of immunotherapeutic agents within liposomes marks a paradigm shift, enabling the design of 'immuno-modulatory hubs' capable of orchestrating precise immune responses while facilitating theranostic applications. The recent COVID-19 pandemic has accelerated research in liposomal-based vaccines and antiviral therapies, underscoring the need for improved delivery mechanisms to overcome challenges like rapid clearance and organ toxicity. Furthermore, we discuss the potential of "smart" liposomes, which can respond to specific disease microenvironments, enhancing treatment efficacy and precision. The integration of artificial intelligence and machine learning in optimizing liposomal designs promises to revolutionize personalized medicine, paving the way for innovative strategies in disease detection and therapeutic interventions. This comprehensive review underscores the significance of ongoing research in liposomal technologies, with implications for future clinical applications and enhanced patient outcomes.

The field of cancer therapeutics has witnessed significant advancements over the past decades, particularly with the emergence of immunotherapy. This chapter traces the transformative journey from traditional antibody-based therapies to the innovative use of nanobodies in the treatment and diagnosis of solid tumors. Nanobodies are the smallest fragments of antibodies derived from camelid immunoglobulins and have redefined the possibilities in cancer theranostics due to their unique structural and functional properties. We provide an overview of the biochemical characteristics of nanobodies that make them particularly suitable for theranostic applications, such as their small size, high stability, enhanced infiltration into the complex tumor microenvironment (TME) and ability to bind with high affinity to epitopes that are inaccessible to conventional antibodies. Further, their ease of modification and functionalization has enabled the development of nanobody-based drug conjugates/toxins and radiolabeled compounds for precise imaging and targeted radiotherapy. We elucidate how nanobodies are being served as valuable tools for prognostic assessment, enabling clinicians to predict disease aggressiveness, monitor treatment response, and stratify patients for personalized therapeutic interventions.

The selective inhibition of key enzymes, such as carbonic anhydrases (CAs IX and XII), which are overexpressed in cancer tissues, has emerged as a promising strategy in cancer research. However, a multitarget approach is often preferred to achieve enhanced therapeutic outcomes. In this study, aryl sulfonamides were conjugated with a thiosemicarbazone moiety to enable dual functionality: the inhibition of CAs and the chelation of metal cations. Several structural factors were systematically modified, including the position of the sulfonamido group, the length of the linker, the nature of the aromatic residue, and the type of substituents. Tumor-associated CAs IX and XII inhibition was evaluated using the stopped-flow CO2 hydrase assay, and the inhibition constants (Ki) were determined. The most promising compounds were further analyzed through molecular docking simulations. Metal chelation capabilities were evaluated using UV-Vis spectroscopy, while antiproliferative activities were measured using the sulforhodamine B (SBR) assay. Additionally, holotomographic 3D microscopy was employed to investigate the mechanisms of cell death. Sulfonamido-derived Schiff bases were synthesized through a three-step procedure that did not require column chromatography purification: (1) isothiocyanation of amino-sulfonamides, (2) nucleophilic addition of hydrazine, and (3) acid-promoted condensation with different aldehydes (benzaldehydes or pyridine-2-carboxaldehyde). The synthesized compounds exhibited inhibition of CAs in the low nanomolar to submicromolar range, with selectivity largely influenced by structural features. Notably, the m-sulfonamide derivative 5b, bearing a pyridin-2-yl residue, demonstrated potent and selective inhibition of CA IX (Ki = 4.9 nM) and XII (Ki = 5.6 nM). Additionally, it efficiently chelated Fe2+, Fe3+, and Cu2+ and showed promising antiproliferative activity (GI50 4.5-10 µM). Mechanistic studies revealed that apoptosis was involved in its mode of action. Therefore, the synergistic integration of sulfonamides and thiosemicarbazones represents an effective strategy for the development of multimodal anticancer agents.

The emergence of antibody-drug conjugates (ADCs) has transformed the treatment landscape of a variety of cancers. ADCs typically consist of three main components: monoclonal antibody, chemical linker, and cytotoxic payload. These integrated therapeutic modalities harness the benefits of each component to provide a therapeutic response that cannot be achieved by conventional chemotherapy. Antibodies play roles in determining tumor specificity through target-mediated uptake, prolonging the circulation half-life of cytotoxic payloads, and providing additional mechanisms of action inherent to the original antibody, thus significantly contributing to the overall performance of ADCs. However, ADCs have unique safety concerns, such as drug-induced adverse events related to the target-mediated uptake of the ADC in normal tissues (so-called "on-target, off-tumor toxicity") and platform toxicity, which are partially derived from limited tumor uptake of antibodies. Identifying suitable target antigens thus impacts the clinical success of ADCs and requires careful consideration, given the multifaceted aspects of this unique treatment modality. This review briefly summarizes the representative roles that antibodies play in determining the efficacy and safety of ADCs. Key considerations for selecting suitable cell surface target antigens for ADC therapy are also highlighted.

An enhanced variant of the antimitotic toxin cryptophycin was conjugated to the anti-Her2 monoclonal antibody (mAb) Trastuzumab upon Michael addition. Either antibodies with freed hinge-region cysteines or THIOMAB formats with engineered cysteines in the mAbs light chain were added to a maleimide derivative of cryptophycin. These Antibody-Drug Conjugates (ADCs) showed retained binding to Her2 positive tumor cells and highly efficient cell killing in double-digit pM range on high Her2-expressing SK-BR-3 cells. Two ADCs (DAR 6, DAR 3) showed superior cell killing of the cell lines JIMT-1 and RT112 with medium receptor expression level in comparison with a DAR 6 MMAE ADC serving as reference. The observed cell cytotoxicity is target-dependent since no impact on cell viability was observed for low Her2-expressing MDA-MB468 cells. Particularly the DAR 3 ADC in THIOMAB format exhibiting desirable biophysical properties and high potency emerged as a promising candidate for further in vivo investigations.

Various therapeutic strategies have been developed to treat Pancreatic Cancer (PaCa). Unfortunately, most efforts have proved unfruitful, as the poor prognosis observed in this disease has only attained little improvement in the past 40 years. Recently, deeper understanding of the immune system and its interaction with malignant tumors have allowed significant advances in immunotherapy. Consistent with this, some of the most promising approaches are those that involve T-cell redirection to the tumor site, such as bispecific T-cell engagers (BiTEs). These recombinant antibodies bridge cytotoxic T-cells to tumor cells, inducing target cell-dependent polyclonal T-cell activation/proliferation, which in turn results in elimination of bound tumor cells. Blinatumomab, an anti-CD19 BiTE, received FDA approval in 2014 for Precursor B-cell Acute Lymphoblastic Leukemia. In the past decade, it has demonstrated impressive clinical benefit in patients with B-cell leukemias; and other T-cell engagers have been FDA-approved for hematological malignancies and other diseases, yet limited effect has been observed with other BiTEs against solid cancers, including PaCa. Nevertheless, on May 2024, Tarlatamab, an anti-DLL3 BiTE was approved by the FDA for extensive small cell lung cancer, becoming the first BiTE for solid tumors. In this review, the generation of BiTEs, therapeutic features, manufacturing issues as well as the remaining challenges and novel strategies of BiTE therapy in the context of PaCa, including the lessons we can learn from the use of BiTEs on other types of cancer will be explored.

The present review provides a detailed and comprehensive discussion on antibody-drug conjugates (ADCs) as an evolving new modality in the current therapeutic landscape of malignant diseases. The principle concepts of targeted delivery of highly toxic agents forsaken as stand-alone drugs are examined in detail, along with the biochemical and technological tools for their successful implementation. An extensive analysis of ADCs' major components is conducted in parallel with their function and impact on the stability, efficacy, safety, and resistance profiles of the immunoconjugates. The scope of the article covers the major classes of currently validated natural compounds used as payloads, with an emphasis on their structural and mechanistic features, natural origin, and distribution. Future perspectives in ADCs' design are thoroughly explored, addressing their inherent or emerging challenges and limitations. The survey also provides a comprehensive overview of the molecular rationale for active tumor targeting of ADC-based platforms, exploring the cellular biology and clinical relevance of validated tumor markers used as a "homing" mechanism in both hematological and solid tumor malignancies.

In recent years, cancer immunotherapy has introduced novel treatments, such as monoclonal antibodies, which have facilitated targeted therapies against tumor cells. Programmed death-1 (PD-1) is an immune checkpoint expressed in T cells that regulates the immune system's activity to prevent over-activation and tissue damage caused by inflammation. However, PD-1 is also expressed in tumor cells and functions as an immune evasion mechanism, making it a therapeutic target to enhance the immune response and eliminate tumor cells. Consequently, immune checkpoint inhibitors (ICIs) have emerged as an option for certain tumor types. Nevertheless, blocking immune checkpoints can lead to immune-related adverse events (irAEs), such as psoriasis and cytokine release syndrome (CRS), as exemplified in the clinical case presented by Zhou et al involving a patient with advanced gastric cancer who received sintilimab, a monoclonal antibody targeting PD-1. Subsequently, the patient experienced exacerbation of psoriasis and CRS. The objective of this editorial article is to elucidate potential immunologic mechanisms that may contribute to the development of CRS and psoriasis in patients receiving ICIs. It is crucial to acknowledge that while ICIs offer superior safety and efficacy compared to conventional therapies, they can also manifest irAEs affecting the skin, gastrointestinal tract, or respiratory system. In severe cases, these irAEs can lead to life-threatening complications such as circulatory shock or multiorgan failure. Consequently, it is recommended that patients receiving ICIs undergo regular monitoring to identify and manage these adverse events effectively.

Naturally occurring protein toxins can derive from bacteria, fungi, plants, and animal venom. Traditionally, toxins are known for their destructive effects on host cells. Despite, and sometimes even because of, these harmful effects, toxins have been used for medical benefits. The prerequisite for the development of toxin-based medications or treatments against toxins is thorough knowledge about the toxin and its underlying mechanism of action. Thus, the toxin of interest must be synthesized. Traditional cell-based production requires high laboratory safety standards and often results in a low total protein yield due to the toxin's harmful, cytotoxic nature. These drawbacks can be circumvented by using cell-free protein synthesis (CFPS), a highly adaptable platform technology relying on cell lysates rather than living cells. This review discusses the current advances in cell-free synthesis of protein toxins as well as their uses and applications for pharmaceutical and diagnostic purposes.

Antibody-drug conjugates (ADCs) are revolutionizing cancer treatment by specific targeting of the cancer cells thereby improving the therapeutic window of the drugs. Nevertheless, they are not free from unwanted toxicities mainly resulting from non-specific targeting and release of the payload. Therefore, the dosing regimen must be optimized through integrated analysis of the risk-benefit profile, to maximize the therapeutic potential. Exposure-response (E-R) analysis is one of the most widely used tools for risk-benefit assessment and it plays a pivotal role in dose optimization of ADCs. However, compared to conventional E-R analysis, ADCs pose unique challenges since they feature properties of both small molecules and antibodies. In this article, we review the E-R analyses that have formed the key basis of dose justification for each of the 12 ADCs approved in the USA. We discuss the multiple analytes and exposure metrics that can be utilized for such analysis and their relevance for safety and efficacy of the treatment. For the endpoints used for the E-R analysis, we were able to uncover commonalities across different ADCs for both safety and efficacy. Additionally, we discuss dose optimization strategies for ADCs which are now a critical component in clinical development of oncology drugs.

Breast cancer remains a leading cause of cancer-related deaths among women worldwide, highlighting the need for novel therapeutic strategies. Trophoblast cell surface antigen 2 (Trop-2), a type I transmembrane glycoprotein highly expressed in various solid tumors including all subtypes of breast cancer, has emerged as a promising target for cancer therapy. This review focuses on recent advancements in Trop-2-targeted antibody-drug conjugates (ADCs) for breast cancer treatment. We comprehensively analyzed the structure and mechanism of action of ADCs, as well as the role of Trop-2 in breast cancer progression and prognosis. Several Trop-2-targeted ADCs, such as Sacituzumab Govitecan (SG) and Datopotamab Deruxtecan (Dato-DXd), have demonstrated significant antitumor activity in clinical trials for both triple-negative breast cancer (TNBC) and hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer. We systematically reviewed the ongoing clinical studies of these ADCs, highlighting their efficacy and safety profiles. Furthermore, we explored the potential of combining Trop-2-targeted ADCs with other therapeutic modalities, including immunotherapy, targeted therapies, and small molecule inhibitors. Notably, Trop-2-targeted ADCs have shown promise in reprogramming the tumor microenvironment through multiple signaling pathways, potentially enhancing antitumor immunity. This review aims to provide new insights and research directions for the development of innovative breast cancer therapies, offering potential solutions to improve treatment outcomes and quality of life for breast cancer patients.

As cancer incidence rises due to an aging population, the importance of precision medicine continues to grow. Antibody-drug conjugates (ADCs) exemplify targeted therapies by delivering cytotoxic agents to specific antigens. Building on this concept, researchers have developed antibody-oligonucleotide conjugates (AOCs), which combine antibodies with oligonucleotides to regulate gene expression. This review highlights the mechanism of AOCs, emphasizing their unique ability to selectively target and modulate disease-causing proteins. It also explores the components of AOCs and their application in tumor therapy while addressing key challenges such as manufacturing complexities, endosomal escape, and immune response. The article underscores the significance of AOCs in precision oncology and discusses future directions, highlighting their potential in treating cancers driven by genetic mutations and abnormal protein expression.

Antibody-drug conjugates (ADC) represent one of the most rapidly expanding treatment modalities in oncology, with 11 ADCs approved by the FDA and more than 210 currently being tested in clinical trials. Spanning over 40 years, ADC clinical development has enhanced our understanding of the multifaceted mechanisms of action for this class of therapeutics. In this article, we discuss key insights into the toxicity, efficacy, stability, distribution, and fate of ADCs. Furthermore, we highlight ongoing challenges related to their clinical optimization, the development of rational sequencing strategies, and the identification of predictive biomarkers. Significance: The development and utilization of ADCs have allowed for relevant improvements in the prognosis of multiple cancer types. Concomitantly, the rise of ADCs in oncology has produced several challenges, including the prediction of their activity, their utilization in sequence, and minimization of their side effects, that still too often resemble those of the cytotoxic molecule that they carry. In this review, we retrace 40 years of development in the field of ADCs and delve deep into the mechanisms of action of these complex therapeutics and reasons behind the many achievements and failures observed in the field to date.

Antibody-drug conjugates (ADCs), chemotherapeutic agents conjugated to an antibody to enhance their targeted delivery to tumors, represent a significant advancement in cancer therapy. ADCs combine the precise targeting capabilities of antibodies and the potent cell-killing effects of chemotherapy, allowing for enhanced cytotoxicity to tumors while minimizing damage to healthy tissues. Here, we provide an overview of the current clinical landscape of ADCs, highlighting 11 U.S. Food and Drug Administration (FDA)-approved products and discussing over 500 active clinical trials investigating newer ADCs. We also discuss some key challenges associated with the clinical translation of ADCs and highlight emerging strategies to overcome these hurdles. Our discussions will provide useful guidelines for the future development of safer and more effective ADCs for a broader range of indications.

In the spectrum of breast malignancies, triple-negative breast cancer is the most widely spreading subtype of breast cancer due to a low availability of therapeutic remedies. Recently, antibody-drug conjugates dramatically resolved the landscape for the treatment of triple-negative breast cancer. This review mainly focuses on the chemistry, structure, mechanism of action, and role of antibody-drug conjugates in triple-negative breast cancer. Datopotecan Deruxtecan (Dato-DXd) is a new-generation ADC showing encouraging results for TNBC. In this review, we have also emphasized TROP-2-directed Datopotamab deruxtecan ADCs to treat triple-negative breast cancer, its synthesis, mechanism of action, pharmacokinetics, pharmacodynamics, adverse events, and their ongoing clinical trials.

Antibody-drug conjugates (ADCs) represent a promising cancer therapy modality which specifically delivers highly toxic payloads to cancer cells through antigen-specific monoclonal antibodies (mAbs). To date, 15 ADCs have been approved and more than 100 ADC candidates have advanced to clinical trials for the treatment of various cancers. Among these ADCs, microtubule-targeting and DNA-damaging agents are at the forefront of payload development. However, several challenges including toxicity and drug resistance limit the potential of this modality. To tackle these issues, multiple innovative payloads such as immunomodulators and proteolysis targeting chimeras (PROTACs) are incorporated into ADCs to enable multimodal cancer therapy. In this review, we describe the mechanism of ADCs, highlight the importance of ADC payloads and summarize recent progresses of conventional and unconventional ADC payloads, trying to provide an insight into payload diversification as a key step in future ADC development.

Background: Biliary tract cancers (BTCs) are aggressive in nature, often presenting asymptomatically until they are diagnosed at an advanced stage. Surgical resection or liver transplantation are potential curative options. However, a large proportion of patients present with incurable locally advanced or metastatic disease and most of these patients are only eligible for palliative chemotherapy or best supportive care. More recently, targeted therapies have proven beneficial in a molecularly selected subgroup of patients with cholangiocarcinoma who have progressed on previous lines of systemic treatment. However, only a minority of patients with BTCs whose tumours harbour specific molecular alterations can access these therapies. Methods: In relation to ADCs, studies regarding use of antibody-drug conjugates in cancer, particularly in BTCs, were searched in Embase (1974 to 2024) and Ovid MEDLINE(R) (1946 to 2024) to obtain relevant articles. Examples of current clinical trials utilising ADC treatment in BTCs were extracted from the ClinicalTrials.gov trial registry. Conclusions: Overall, this review has highlighted that ADCs have shown encouraging outcomes in cancer therapy, and this should lead to further research including in BTCs, where treatment options are often limited. The promising results observed with ADCs in various cancers underscore their potential as a transformative approach in oncology, warranting continued exploration and development and the need for education on the management of their specific toxicities. By addressing current challenges and optimising ADC design and application, future studies could potentially improve treatment outcomes for patients with BTCs and beyond, potentially in both early and advanced stage settings.

Using the principle of "Magic Bullet", a cisplatin-derived platinum(IV) prodrug heterobimetallic Pt(IV)-Ru(II) complex, cis,cis,trans-[Pt(NH3)2Cl2{Ru(tpy-BODIPY)(tpy-COO)}(biotin)]Cl2 (Pt-Ru-B, 2), having two axial ligands, namely, biotin as water-soluble B-vitamin for enhanced cellular uptake and a BODIPY-ruthenium(II) (Ru-B, 1) photosensitizer having N,N,N-donor tpy (4'-phenyl-2,2':6',2″-terpyridine) bonded to boron-dipyrromethene (BODIPY), is developed as a "Platin Bullet" for targeted photodynamic therapy (PDT). Pt-Ru-B exhibited intense absorption near 500 nm and emission near 513 nm (λex = 488 nm) in a 10% dimethyl sulfoxide-Dulbecco's phosphate-buffered saline medium (pH 7.2). The BODIPY complex on light activation generates singlet oxygen as the reactive oxygen species (ROS) giving a quantum yield (ΦΔ) of ∼0.64 from 1,3-diphenylisobenzofuran experiments. Pt-Ru-B exhibited preferential cellular uptake in cancer cells over noncancerous cells. The dichlorodihydrofluorescein diacetate assay confirmed the generation of cellular ROS. Confocal images revealed its mitochondrial internalization. Pt-Ru-B showed submicromolar photocytotoxicity in visible light (400-700 nm) in A549 and multidrug-resistant MDA-MB-231 cancer cells. It remained nontoxic in the dark and less toxic in nontumorigenic cells. Cellular apoptosis and alteration of the mitochondrial membrane potential were evidenced from the respective Annexin V-FITC/propidium iodide assay and JC-1 dye assay. A wound healing assay using A549 cells and Pt-Ru-B revealed inhibition of cancer cell migration, highlighting its potential as an antimetastatic agent.

The crystal structure of a previously reported antimicrobial RuII complex that targets bacterial DNA is presented. Studies utilizing clinical isolates of Gram-negative bacteria that cause catheter-associated urinary tract infection, (CA)UTI, in media that model urine and plasma reveal that good antimicrobial activity is maintained in all conditions tested. Experiments with a series of Staphylococcus aureus clinical isolates show that, unlike the majority of previously reported RuII-based antimicrobial leads, the compound retains its potent activity even in MRSA strains. Furthermore, experiments using bacteria in early exponential growth and at different pHs reveal that the compound also retains its activity across a range of conditions that are relevant to those encountered in clinical settings. Combinatorial studies involving cotreatment with conventional antibiotics or a previously reported analogous dinuclear RuII complex showed no antagonistic effects. In fact, although all combinations show distinct additive antibacterial activity, in one case, this effect approaches synergy. It was found that the Galleria Mellonella model organism infected with a multidrug resistant strain of the ESKAPE pathogen Acinetobacter baumannii could be successfully treated and totally cleared within 48 h after a single dose of the lead complex with no detectable deleterious effect to the host.

Cancers only develop if they escape immunosurveillance, and the success of cancer immunotherapies relies in most cases on their ability to restore effector T-cell functions, particularly IFNγ production. Revolutionizing the treatment of many cancers, immunotherapies targeting immune checkpoints such as PD1 can increase survival and cure patients. Unfortunately, although immunotherapy has greatly improved the prognosis of patients, not all respond to anti-PD1 immunotherapy, making it crucial to identify alternative treatments that could be combined with current immunotherapies to improve their effectiveness. Here, we show that iron supplementation significantly boosts T-cell responses in vivo and in vitro. The boost was associated with a metabolic reprogramming of T cells in favor of lipid oxidation. We also found that the "adjuvant" effect of iron led to a marked slowdown of tumor cell growth after tumor cell line transplantation in mice. Specifically, our results suggest that iron supplementation promotes antitumor responses by increasing IFNγ production by T cells. In addition, iron supplementation improved the efficacy of anti-PD1 cancer immunotherapy in mice. Finally, our study suggests that, in patients with cancer, the quality and efficacy of the antitumor response following anti-PD1 immunotherapy may be modulated by plasma ferritin levels. In summary, our results suggest the benefits of iron supplementation on the reactivation of antitumor responses and support the relevance of a fruitful association between immunotherapy and iron supplementation.

Antibody-drug conjugates (ADCs) consist of antibodies, linkers and payloads. They offer targeted delivery of potent cytotoxic drugs to tumor cells, minimizing off-target effects. However, the therapeutic efficacy of ADCs is compromised by heterogeneity in the drug-to-antibody ratio (DAR), which impacts both cytotoxicity and pharmacokinetics (PK). Additionally, the emergence of drug resistance poses significant challenges to the clinical advancement of ADCs. To overcome these limitations, a variety of strategies have been developed, including the design of multi-specific drugs with accurate DAR. This review critically summarizes the current challenges faced by ADCs, categorizing key issues and evaluating various innovative solutions. We provide an in-depth analysis of the latest methodologies for achieving homogeneous DAR and explore design strategies for multi-specific drugs aimed at combating drug resistance. Our discussion offers a current perspective on the advancements made in refining ADC technologies, with an emphasis on enhancing therapeutic outcomes.

Drug conjugates are obtained from tumor-located vectors connected to cytotoxic agents via linkers, which are designed to deliver hyper-toxic payloads directly to targeted cancer cells. These drug conjugates include antibody-drug conjugates (ADCs), peptide-drug conjugates (PDCs), small molecule-drug conjugates (SMDCs), nucleic acid aptamer-drug conjugates (ApDCs), and virus-like drug conjugate (VDCs), which show great therapeutic value in the clinic. Drug conjugates consist of a targeting carrier, a linker, and a payload. Payloads are key therapy components. Cytotoxic molecules and their derivatives derived from natural products are commonly used in the payload portion of conjugates. The ideal payload should have sufficient toxicity, stability, coupling sites, and the ability to be released under specific conditions to kill tumor cells. Microtubule protein inhibitors, DNA damage agents, and RNA inhibitors are common cytotoxic molecules. Among these conjugates, cytotoxic molecules of natural origin are summarized based on their mechanism of action, conformational relationships, and the discovery of new derivatives. This paper also mentions some cytotoxic molecules that have the potential to be payloads. It also summarizes the latest technologies and novel conjugates developed in recent years to overcome the shortcomings of ADCs, PDCs, SMDCs, ApDCs, and VDCs. In addition, this paper summarizes the clinical trials conducted on conjugates of these cytotoxic molecules over the last five years. It provides a reference for designing and developing safer and more efficient conjugates.

To maximize therapeutic effects and minimize unwanted effects, the interest in drug targeting to the endoplasmic reticulum (ER) or Golgi apparatus (GA) has been recently growing because two organelles are distributing hubs of cellular building/signaling components (e.g., proteins, lipids, Ca2+) to other organelles and the plasma membrane. Their structural or functional damages induce organelle stress (i.e., ER or GA stress), and their aggravation is strongly related to diseases (e.g., cancers, liver diseases, brain diseases). Many efforts have been developed to image (patho)physiological functions (e.g., oxidative stress, protein/lipid-related processing) and characteristics (e.g., pH, temperature, biothiols, reactive oxygen species) in the target organelles and to deliver drugs for organelle disruption using organelle-targeting moieties. Therefore, this review will overview the structure, (patho)physiological functions/characteristics, and related diseases of the organelles of interest. Future direction on ER or GA targeting will be discussed by understanding current strategies and investigations on targeting, imaging/sensing, and therapeutic systems.

Hepato-Pancreato-Biliary (HPB) malignancies constitute a highly aggressive group of cancers that have a dismal prognosis. Patients not amenable to curative intent surgical resection are managed with systemic chemotherapy which, however, confers little survival benefit. Antibody-Drug Conjugates (ADCs) are tripartite compounds that merge the intricate selectivity and specificity of monoclonal antibodies with the cytodestructive potency of attached supertoxic payloads. In view of the unmet need for drugs that will enhance the survival rates of HPB cancer patients, the assessment of ADCs for treating HPB malignancies has become the focus of extensive clinical and preclinical investigation, showing encouraging preliminary results. In the current review, we offer a comprehensive overview of the growing body of evidence on ADC approaches tested for HPB malignancies. Starting from a concise discussion of the functional principles of ADCs, we summarize here all available data from preclinical and clinical studies evaluating ADCs in HPB cancers.

Malignant tumors remain a primary cause of human mortality. Among the various treatment modalities for neoplasms, tumor vaccines have consistently shown efficacy and promising potential. These vaccines offer advantages such as specificity, safety, and tolerability, with mRNA vaccines representing promising platforms. By introducing exogenous mRNAs encoding antigens into somatic cells and subsequently synthesizing antigens through gene expression systems, mRNA vaccines can effectively induce immune responses. Katalin Karikó and Drew Weissman were awarded the 2023 Nobel Prize in Physiology or Medicine for their great contributions to mRNA vaccine research. Compared with traditional tumor vaccines, mRNA vaccines have several advantages, including rapid preparation, reduced contamination, nonintegrability, and high biodegradability. Tumor-targeted therapy is an innovative treatment modality that enables precise targeting of tumor cells, minimizes damage to normal tissues, is safe at high doses, and demonstrates great efficacy. Currently, targeted therapy has become an important treatment option for malignant tumors. The application of mRNA vaccines in tumor-targeted therapy is expanding, with numerous clinical trials underway. We systematically outline the targeted delivery mechanism of mRNA vaccines and the mechanism by which mRNA vaccines induce anti-tumor immune responses, describe the current research and clinical applications of mRNA vaccines in tumor-targeted therapy, and forecast the future development trends of mRNA vaccine application in tumor-targeted therapy.