{"title":"Beyond ADCs: Antibody-encapsulated drug for targeted cancer therapy.","authors":"Linrong Li, Armando Giuliano, Qiang Sun, Xiaojiang Cui, Yuan Yuan","doi":"10.1016/j.clnves.2026.100087","DOIUrl":"10.1016/j.clnves.2026.100087","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) have transformed cancer treatment by covalently linking the monoclonal antibody with cytotoxic payload, yet their clinical potential remains constrained by intrinsic limitations: heterogeneous drug-to-antibody ratios, linker instability, manufacturing complexity, and drug resistance. These challenges highlight the need for fundamentally different drug formulation and delivery platforms. Antibody-encapsulated drugs (AEDs) leverage the single protein encapsulation technology to enable one antibody to noncovalently encapsulate a predefined number of payload molecules. AEDs allow for a fixed drug-to-antibody ratio, mitigate premature drug release, simplify manufacturing, and expand the range of compatible payloads and protein molecules. Preclinical investigation of trastuzumab-encapsulated actinomycin D, a HER2-targeted AED, has demonstrated potent antitumor activity across cancer models with varying HER2 expression levels, alongside a favorable toxicity profile in animal models. The broader translational feasibility of the single protein encapsulation platform is further supported by ongoing clinical trials of albumin-encapsulated therapeutics. Together, these advances position AED as a promising next-generation targeted cancer therapy that complements and potentially extends beyond conventional ADCs, offering a compelling strategy to overcome existing resistance mechanisms and therapeutic limitations.</p>","PeriodicalId":520460,"journal":{"name":"Cell investigation","volume":"2 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13502141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148815398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell investigationPub Date : 2025-12-01Epub Date: 2025-08-07DOI: 10.1016/j.clnves.2025.100035
Qingxiao Song, Kiranj Chaudagar, Xi Zhang, Edmund K Waller
{"title":"T cell-macrophage crosstalk in GVHD and cancer immunotherapy.","authors":"Qingxiao Song, Kiranj Chaudagar, Xi Zhang, Edmund K Waller","doi":"10.1016/j.clnves.2025.100035","DOIUrl":"10.1016/j.clnves.2025.100035","url":null,"abstract":"<p><p>The immune microenvironment is pivotal in regulating two complementary adverse outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT): graft-versus-host disease (GVHD) and tumor progression. While GVHD manifests as immune hyperactivation, causing tissue injury, cancer subverts immune surveillance by immunosuppressive strategies. Although initial studies focused on distinct mechanisms involving T-B interactions in GVHD and T-tumor cell interactions in cancer immunotherapy, it is increasingly clear that dysregulated T cell-macrophage interactions drive immunopathology in GVHD, with comparative insights into cancer immunotherapy. Here, we discuss recent advances and elucidate three core regulatory paradigms governing these immunostimulatory vs immunosuppressive interactions: (1) cytokine networks, (2) immune checkpoint regulation, and (3) metabolic reprogramming. Based on functional pre-clinical studies and clinical evidence, we describe the dynamic, reciprocal immune crosstalk between T cells and macrophages that underlies GVHD after allo-HSCT and the immunosuppressive tumor microenvironment. Finally, we outline emerging therapeutic approaches that target T cell and macrophage interactions to prevent GVHD and overcome an immunologically \"cold\" microenvironment in the cancer.</p>","PeriodicalId":520460,"journal":{"name":"Cell investigation","volume":"1 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13249391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148221519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell investigationPub Date : 2025-06-01Epub Date: 2025-06-06DOI: 10.1016/j.clnves.2025.100023
Lianjun Zhang, Yidan Lou, Weini Li, Hongshan Guo, Le Xuan Truong Nguyen, Zhenhua Chen
{"title":"RNA m<sup>6</sup>A modification: a key regulator in normal and malignant processes.","authors":"Lianjun Zhang, Yidan Lou, Weini Li, Hongshan Guo, Le Xuan Truong Nguyen, Zhenhua Chen","doi":"10.1016/j.clnves.2025.100023","DOIUrl":"10.1016/j.clnves.2025.100023","url":null,"abstract":"<p><p>The dedicated control of gene abundance is essential for both biological and pathological processes in mammals. Multiple layers of gene expression regulation, including transcriptional, post-transcriptional, translational, and post-translational regulation, collectively determine the highly dynamic equilibrium of functional protein abundance. Epigenetic modifications play indispensable roles in fine-tuning gene expression at either DNA, RNA, or protein level. To date, over 170 chemical modifications have been identified in RNA, with <i>N</i> <sup>6</sup>-methyladenosine (m<sup>6</sup>A) emerging as the most abundant and functionally significant modification in messenger RNA (mRNA). Many proteins have been identified as m<sup>6</sup>A-related proteins such as \"writer\" (deposition), \"eraser\" (removal) and \"reader\" (recognition). The dynamic m<sup>6</sup>A abundance (controlled by writer and eraser) together with reader proteins determine mRNA fate/metabolism, including transcription, alternative splicing, nuclear export, mRNA stability, and translation. Here, we summarize the latest findings on m<sup>6</sup>A-associated molecular mechanisms, emerging technologies for mapping m<sup>6</sup>A, and the roles of m<sup>6</sup>A-related proteins in both normal and malignant contexts. We further discuss/review the controversial opinions and open debates, and translational/clinical potential of m<sup>6</sup>A/m<sup>6</sup>A-related proteins as therapeutic targets, highlighting remaining questions and research directions in RNA m<sup>6</sup>A modifications.</p>","PeriodicalId":520460,"journal":{"name":"Cell investigation","volume":"1 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12306181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144746690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell investigationPub Date : 2025-03-01Epub Date: 2025-02-26DOI: 10.1016/j.clnves.2025.100008
Lianjun Zhang, Cunte Chen, Jia Feng, Hongyu Zhang, Le Xuan Truong Nguyen, Zhenhua Chen
{"title":"The role of YTHDF2 in anti-tumor immunity.","authors":"Lianjun Zhang, Cunte Chen, Jia Feng, Hongyu Zhang, Le Xuan Truong Nguyen, Zhenhua Chen","doi":"10.1016/j.clnves.2025.100008","DOIUrl":"https://doi.org/10.1016/j.clnves.2025.100008","url":null,"abstract":"<p><p>RNA <i>N</i> <sup>6</sup>-methyladenosine (m<sup>6</sup>A) modification has been identified as the most abundant RNA modification and plays crucial roles in both physiological and pathological processes. YTHDF2 was the first identified reader protein that can recognize m<sup>6</sup>A modification and recent studies also revealed its ability to bind 5-methylcytidine (m<sup>5</sup>C) modification. YTHDF2 shows a dual binding capacity to both m<sup>6</sup>A and m<sup>5</sup>C, which leads to opposite mRNA outcomes. Multiple studies have highlighted the critical roles of YTHDF2 in tumor development and tumor microenvironment. Emerging findings showed that YTHDF2 plays critical roles in immune regulation, impacting T cell, B cell, NK cell, macrophage, innate/adaptive anti-tumor immune responses, and T-cell based immunotherapy. Inhibitors have been developed to target YTHDF2, which showed potential efficacy in tumor treatment. Herein, we reviewed the molecular mechanism of YTHDF2 and its roles in tumors, immune cells, and tumor microenvironment.</p>","PeriodicalId":520460,"journal":{"name":"Cell investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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