Aug 2026· Journal of Peptide Science· Vol 32· 0 citations· 193 references
Medicine
TL;DR
This review systematically summarizes advancements in peptide‐based therapeutics for solid tumors from 2020 to 2025, and highlights the transformative role of artificial intelligence (AI) in peptide design and discovery.
Abstract
Solid tumors, the most prevalent form of malignancy, pose therapeutic challenges distinct from hematologic malignancies due to their complex biology, including high tumor heterogeneity, a dense extracellular matrix (ECM), an immunosuppressive tumor microenvironment (TME), and multifaceted drug resistance. Peptide drugs have emerged as a focal point in precision oncology, combining the deep tissue penetration of small molecules with the high target specificity, low immunogenicity, and sequence designability of antibodies. This review systematically summarizes advancements in peptide‐based therapeutics for solid tumors from 2020 to 2025. These agents are categorized by function into five classes: tumor‐homing peptides, surface receptor antagonist/inhibitory peptides, interfering peptides, peptide vaccines, and cell‐penetrating peptides as delivery tools. We also highlight the transformative role of artificial intelligence (AI) in peptide design and discovery. Finally, we discuss outcomes from clinical trials of peptide drugs in solid tumors, underscoring their potential as multifunctional agents in this setting.
Background: Antibody-drug conjugates (ADCs) have transformed the treatment of solid tumors by combining the tumor specificity of monoclonal antibodies with highly potent cytotoxic payloads. Advances in ADC engineering have expanded their clinical applications while addressing limitations of conventional chemotherapy and targeted therapies.Methods: We conducted a comprehensive narrative review of the molecular mechanisms, structural design, resistance pathways, clinical translation, and emerging engineering strategies of ADCs in solid tumors, integrating evidence from preclinical and clinical studies.Results: ADC efficacy is governed by antigen selection, linker chemistry, payload characteristics, and drug-to-antibody ratio, which collectively influence pharmacokinetics, tumor penetration, intracellular trafficking, and payload release. Key mechanisms include receptor-mediated internalization, lysosomal processing, bystander killing, immune modulation, and interactions with the tumor microenvironment. Major resistance mechanisms comprise antigen heterogeneity, impaired intracellular trafficking, drug efflux, adaptive DNA repair, and stromal barriers. Emerging innovations-including site-specific conjugation, bispecific and conditionally activated ADCs, novel payloads, biomarker-guided patient selection, and rational combination therapies-are enhancing therapeutic efficacy and expanding targetable tumors.Conclusion: Continued advances in molecular engineering and precision biomarker strategies are redefining ADCs as versatile platforms for precision oncology and may enable broader, potentially tumor-agnostic, applications in solid tumors.
H. P. Luqmana, A. Ashariati, M. Savitri et al.· Immunological Investigations· 0 citations
Lung cancer is currently the most frequently diagnosed malignancy worldwide, accounting for approximately 12.4% of all cancers and, despite major advances in molecularly targeted therapies and immunotherapy, represents the leading cause of cancer-related mortality, In recent years, antibody–drug conjugates (ADCs) have emerged as a novel therapeutic strategy, combining the specificity of monoclonal antibodies with the potent cytotoxic activity of highly active payloads to selectively target tumor cells while limiting systemic toxicity. This narrative review summarizes the current role of ADCs in lung cancer, with particular focus on their structural components, mechanisms of action, and the biological features that determine treatment efficacy. We discuss the rationale for targeting established and emerging antigens in non-small cell and small cell lung cancer, including HER2, TROP2, c-MET, HER3, CEACAM5, DLL3, and other promising targets currently under clinical investigation. The principal mechanisms of primary and acquired resistance are also reviewed, including antigen modulation, altered intracellular trafficking, lysosomal dysfunction, drug efflux, tumor microenvironment-mediated immune suppression, and intratumor heterogeneity. In addition, we provide an overview of the safety profile of ADCs, highlighting the most clinically relevant adverse events and their underlying biological mechanisms. We also examine the evolving landscape of predictive biomarkers beyond antigen expression, including genomic, transcriptomic, proteomic, and liquid biopsy-based approaches, together with emerging spatial and single-cell technologies that may improve patient selection. Finally, we discuss future directions in the field, including novel payloads, next-generation linker technologies, bispecific ADCs, combination strategies, and personalized ADC development. Overall, ADCs are rapidly reshaping the therapeutic landscape of lung cancer. Continued optimization of drug design, biomarker-driven patient selection, and a deeper understanding of resistance mechanisms will be essential to fully realize their clinical potential.
P. Paliogiannis, G. Fara, A. Zinellu et al.· Current Issues in Molecular...· 0 citations
Antibody-drug conjugates (ADCs) are rapidly evolving from conventional cytotoxic delivery systems into multifunctional, immune-integrated therapeutic platforms. Highlights from the 2026 American Association for Cancer Research (AACR) Annual Meeting demonstrate significant advances in ADC design, including dual- and multi-payload constructs, multispecific targeting strategies, and immunostimulatory payloads. These innovations aim to overcome key limitations such as tumor heterogeneity, resistance, and systemic toxicity. Novel approaches targeting the tumor microenvironment, including depletion of regulatory T cells and tumor-associated macrophages, further expand the therapeutic scope of ADCs beyond direct tumor cell killing. In parallel, integration with emerging modalities such as engineered CD16-enhanced natural killer T (NKT) cells underscores the potential for synergy between ADCs and cellular immunotherapies. Advances in AI-guided target discovery and antibody engineering are also enhancing tumor selectivity and internalization. Collectively, these developments highlight a paradigm shift toward precision, multi-mechanistic ADCs with the potential to improve clinical outcomes across diverse cancer types.
Pediatric solid tumors continue to pose a major therapeutic challenge, with survival gains lagging behind those achieved in pediatric hematologic malignancies. While traditional approaches have focused on dose escalation and intensification of systemic therapies to improve survival, this strategy is often limited by significant short- and long-term morbidity from intensive multimodal treatment. Because children have developing organs and decades of life ahead, therapeutic strategies must balance durable tumor control with preservation of neurodevelopment, organ function, and quality of life. Immunotherapy has generated significant interest as an alternative to dose escalation; however, clinical translation in pediatric solid tumors has been limited by antigen heterogeneity, tumor plasticity, immune-cold or immune-excluded phenotypes, and a profoundly immunosuppressive tumor microenvironment. Bioengineered cellular therapies, particularly chimeric antigen receptor (CAR) T cells and CAR-modified natural killer (CAR NK) cells, provide a modular platform to address these barriers through synthetic receptor design, multi-antigen targeting, controlled activation, and improved trafficking to anatomically restricted sites such as the brain. However, engineering advances alone are unlikely to achieve durable benefit without parallel integration of quantitative in vivo monitoring capable of reporting biodistribution, persistence, and functional engagement. Non-invasive imaging and measurement-enabled approaches can provide mechanistic insight into therapeutic performance, discriminate between delivery failure and functional dysfunction, and support rational iteration of construct design, dosing, and route of administration. In this perspective, we review the current status of CAR T and CAR NK therapies in pediatric solid malignancies, outline key biological and engineering challenges, and propose a pediatric-centered development framework that integrates controllable cell engineering with quantitative, non-invasive assessment of in vivo behavior. By embedding measurement into the therapeutic design loop and prioritizing long-term safety and developmental outcomes alongside efficacy, next-generation engineered cell therapies may evolve toward adaptable, precision-guided systems capable of improving both survival and quality of life for children.
Ana M. Sandoval-Castellanos, Yumin Ahn, Robert J Canter et al.· Progress in Biomedical Engin...· 0 citations
This review synthesizes literature spanning 1990-2026 on advances in ADC design and their clinical and translational implementation in breast cancer to support reframing antigen selection as a system-level challenge, supported by delivery-focused engineering, precision-medicine-driven trial design, and adaptive methodology.
Callum Chapman, A. Cheung, G. B. Armstrong et al.· Expert Opinion on Drug Deliv...· 0 citations
Brain cancer is one of the most challenging malignancies and a major contributor to worldwide morbidity and mortality. Glioblastoma, the most aggressive adult brain tumor, is associated with poor prognosis despite conventional therapies such as surgery, chemotherapy, and radiotherapy, which often result in severe toxicity and long-term side effects. Immunotherapy holds the potential to provide durable and specific anti-tumor responses; however, its success in brain cancer is hindered by obstacles such as the blood-brain barrier, immunosuppressive tumor microenvironment, and tumor heterogeneity. Nanomedicine offers a powerful approach to overcoming these barriers through targeted and efficient drug delivery. Nanotechnology-based platforms, including lipid-based, polymeric, and inorganic nanoparticles, have demonstrated superior therapeutic efficacy compared to free drugs, with several formulations advancing into clinical trials. Among these, nanotechnology-enabled vaccines represent an emerging frontier, capable of enhancing antigen presentation, stimulating strong immune responses, and overcoming tumor-induced immunosuppression. By combining the precision of nanocarriers with the long-lasting protection of vaccines, nano-vaccines hold great potential to transform brain cancer immunotherapy. Recent studies also suggest that integrating artificial intelligence (AI) with nanotechnology could further enhance the design, targeting, and effectiveness of immunotherapies. Moreover, AI is revolutionizing treatment development by enabling the prediction of immunogenicity, immune responses, and optimizing formulation design and dosing strategies. These advancements collectively accelerate the development and enhance the precision and efficiency of immunotherapy. Hence, this review discusses current nanotechnology-based immunotherapies and highlights the emerging role of integrating AI in vaccine development as next-generation strategies for improving outcomes in brain cancer treatment.
Alia Syazana Mohd Roslei, H. Huri, D. A. Pratama et al.· Journal of the Egyptian Nati...· 0 citations