Acta Pharmaceutica Sinica B

Syringin disrupts the DLAT/MYC axis to dampen TAM polarization and suppress hepatocellular carcinoma progression

Acta Pharmaceutica Sinica B. 2026, 16(6): 3680-3697.

Tumor-associated macrophages (TAMs) are pivotal drivers of hepatocellular carcinoma (HCC) progression, and blocking TAM M2 polarization has the potential to dampen tumor microenvironment remodeling. In this study, we screened a series of phenylethanoid and phenylpropanoid glycosides and identified syringin as a natural compound capable of inhibiting M2 polarization while promoting M1 polarization in macrophages. Single-cell RNA sequencing confirmed that syringin reduced TAM M2 polarization and significantly impaired tumor microenvironment remodeling. In detail, syringin indirectly reduced the stability of MYC proto-oncogene protein (MYC), which is required for driving a broad set of targets, including Arg1, Il10, Ym1, Mrc1, and Cd274. Using affinity-based protein profiling (ABPP), we revealed dihydrolipoamide S-acetyltransferase (DLAT) as a direct target of syringin. DLAT possesses protein acetyltransferase activity that acetylates MYC at K148. Syringin bound DLAT at residues R430 and N576 and disrupted the DLAT/MYC axis, thereby blocking MYC acetylation and promoting the ubiquitination and degradation of MYC protein. Additionally, syringin enhanced the efficacy of programmed cell death protein 1 blockade in mouse and patient-derived xenograft models, offering a potential adjunctive agent for HCC.

Targeting frizzled receptors (FZDs) for anti-tumor therapy: From orthosteric to allosteric inhibition

Acta Pharmaceutica Sinica B. 2026, 16(6): 3315-3342.

Frizzled receptors (FZDs) have emerged as pivotal regulators in cancer biology, orchestrating key oncogenic processes such as tumor metastasis, therapy resistance, and stemness through canonical WNT/β-catenin and noncanonical WNT/PCP and WNT/Ca²⁺ signaling pathways. Their overexpression in diverse malignancies and cell surface localization make FZDs compelling therapeutic targets. Yet, clinical translation of FZD-targeted therapies has been hindered by limited efficacy and poor subtype specificity of FZD orthosteric inhibitors. In this review, we provide a comprehensive and systematic analysis of FZD biology by tracing its discovery history, elucidating its conserved structural features, and deciphering its context-dependent roles in WNT signaling. We propose novel insights into the multifaceted roles of FZD in tumorigenesis, positioning it as a driver of cancer progression. We emphasize the urgent need for developing subtype-selective targeting strategies for FZD, critically assess the challenges of achieving binding specificity within highly homologous extracellular domains, and summarize cutting-edge advances in structure-based design of FZD negative allosteric modulators. This study establishes a strategic framework for precision targeting of the FZD family, paving the way for developing more efficient, mechanism-driven, and potentially transformative anticancer therapies.

Targeting cytokine/chemokine signaling to convert immunologically cold tumors into hot: Emerging strategies in cancer immunotherapy

Acta Pharmaceutica Sinica B. 2026, 16(6): 3292-3314.

The field of cancer immunotherapy has undergone significant advancements in recent years, leading to a paradigm shift in treatment methodologies. However, “cold” tumors, characterized by low immune cell infiltration and an immunosuppressive tumor microenvironment (TME), present considerable therapeutic challenges. In contrast to “hot” tumors, which exhibit vigorous immune activity and responsiveness to immune checkpoint inhibitors, “cold” tumors evade immune surveillance through mechanisms such as impaired antigen expression and restricted T-lymphocyte infiltration. This immune evasion is closely linked to the dysregulation of cytokines and chemokines, which shape the TME and orchestrate immune responses. This review delineates the immune escape mechanisms of cold tumors, with particular emphasis on the role of cytokines/chemokines in modulating the TME. Here we will explore advanced therapeutic strategies that employ engineered chemokines/cytokines (e.g., IL-2 muteins such as Neo-2/15, IL-15/IL-15Rα complexes, and CAR-T cells expressing CXCL9/10), nanoparticle-based delivery systems (e.g., lipid nanoparticles, PLGA nanoparticles, and chitosan-based carriers for targeted cytokine/chemokine delivery), and combination therapies. These strategies aim to remodel the TME to enhance immune infiltration. Emerging therapies designed to transform cold tumors into immunologically active phenotypes through the modulation of cytokines and chemokines are discussed. Finally, the review highlights the ongoing challenges and future directions in using cytokine/chemokine modulation to overcome the limitations of current treatments, emphasizing their transformative potential in addressing the unmet needs of cancer immunotherapy.

Engineered extracellular vesicles for combinatorial cancer therapy and imaging

Acta Pharmaceutica Sinica B. 2026, 16(6): 3540-3581.

Cancer treatment has advanced significantly over the past few decades, resulting in improved patient survival outcomes. However, challenges like drug resistance, off-target effects, and systemic toxicity continue to persist. These underscore the importance of modified extracellular vesicles (EVs) as a versatile and innovative platform for delivering combination therapies for cancer. This review highlights the utilization of biocompatible engineered EVs to inhibit cancer progression with reduced side effects. Further, outlining the promising approach to cancer treatment through combination therapies and imaging-guided strategies. Additionally, this review explored the biogenesis and various sources of EVs, which provides clear insights into future directions.

Recent advances in antiviral drugs for Chikungunya virus (CHIKV): Targets, mechanisms, and development strategies

Xiaowen Jiang, Yudan Zhao, Hongyuan Lu, Keqiang Li, Huiyuan Gao

Acta Pharmaceutica Sinica B. 2026, 16(6): 3257-3291.

Chikungunya virus (CHIKV), an alphavirus transmitted by Aedes mosquitoes, has frequently caused outbreaks in tropical and subtropical regions worldwide, posing a significant public health threat. CHIKV infection leads to chikungunya fever, characterized by fever, rash, and persistent joint pain, with approximately 30%-40% of patients developing chronic arthritis that severely impacts quality of life. Currently, no specific antiviral drugs or vaccines against CHIKV have been approved for clinical use, highlighting the urgency of drug development. This review systematically summarizes recent progress in antiviral research on CHIKV, focusing on key target proteins in the viral life cycle, such as non-structural proteins nsP1, nsP2, nsP3, nsP4, and structural protein E1-E2 complexes, as well as the mechanisms of action of their inhibitors. We analyze the current research status of various anti-CHIKV compounds, including suramin, baicalin, halofuginone, betulinic acid, andrographolide, and itraconazole. Additionally, we summarize host-directed antiviral strategies targeting pathways such as host cell oxidative folding, Na⁺/K⁺-ATPase, and MAPK signaling. This review aims to establish a theoretical foundation and outline potential research directions for the development of CHIKV-related therapeutics, thereby facilitating the discovery of effective treatment strategies against this pathogen.

Organoids, organ-on-a-chip, and microtumors: Biomimetic 3D tumor models advancing drug development and precision medicine

Acta Pharmaceutica Sinica B. 2026, 16(6): 3343-3371.

The rising global cancer burden underscores the urgent need for more effective drug development and personalized therapies. Conventional screening models, such as 2D cell lines and patient-derived xenografts, fail to adequately recapitulate the architecture, heterogeneity, and microenvironment of human tumors, limiting their clinical translatability. In response, human-derived biomimetic platforms have emerged. Organoids and organ-on-a-chip preserve key tumor genetics and stimulate dynamic, physiologically relevant microenvironments, whereas microtumors are distinguished by high biological fidelity. Microtumors uniquely retain the native tumor ecosystem, capture a broader spectrum of intratumoral heterogeneity, and, critically, maintain a functional immune microenvironment. Together, these systems enable drug screening that more faithfully reflects the clinical context, with strong potential to raise drug development success rates and support individualized therapy. This review consolidates the cutting-edge advancements and critical challenges associated with these models in drug development, precision medicine, and clinical translation. Furthermore, it envisions how Artificial Intelligence (AI) can drive its intelligent evolution, aiming to provide a robust evidentiary basis and practical reference for research and clinical practice, thereby propelling the field of precision oncology into a new era.

Where and when to strike: Spatiotemporally controlled smart nanomedicines for precision antibacterial therapy

Acta Pharmaceutica Sinica B. 2026, 16(6): 3372-3399.

The global rise of antimicrobial resistance calls for new therapeutic approaches that move beyond conventional broad-spectrum antibiotics toward precision-guided nanotherapeutics. This review examines how smart antibacterial nanomedicines achieve better therapeutic outcomes through two key control dimensions: Spatial precision (where) and temporal activation (when). We first discuss active targeting strategies that direct therapeutic payloads to infection sites while sparing healthy tissues. We then analyze microenvironment-responsive mechanisms that keep therapeutic agents inactive until they encounter specific pathological signals. Moving beyond a simple catalog of material properties, we propose a “Hierarchical Intelligence Framework” that organizes nanoparticles along a spectrum of increasing complexity—from basic ligand-guided systems to integrated, logic-responsive nanodevices operating through “Target-Trigger-Treat” protocols. By examining design principles and practical challenges in pharmaceutical development, this work outlines a path toward resistance-overcoming nanomedicines that may reshape infection management in the coming decades.

Advances in immune cell-based therapeutic agents for the treatment of inflammation-related diseases

Yuxin Yang, Jinhu Liu, Jie Liu, Suyun Wei, Xiaohui Kong, Weiwei Mu, Yongjun Liu, Na Zhang

Acta Pharmaceutica Sinica B. 2026, 16(5): 2794-2837.

Inflammation-related diseases account for over 50% of global disease-associated mortality; the core pathological mechanisms of these diseases are closely linked to functional dysregulation of immune cells such as macrophages and T cells. Aberrantly activated immune cells excessively secrete inflammatory mediators, which drive chronic inflammatory cascades and trigger irreversible tissue damage. In recent years, immune cell-based therapeutic agents (ICTAs) have garnered significant attention due to their inherent targeting specificity and immunomodulatory capabilities, encompassing whole immune cells, cell membranes, or extracellular vesicles serving as active therapeutics or delivery carriers. This review systematically elaborates on strategies for constructing ICTAs through nanoengineering, genetic engineering, and membrane-fused engineering, while outlining their integrating applications with other delivery devices. Furthermore, we summarize the preclinical and clinical trial advancements of ICTAs in various diseases such as tumors, rheumatoid arthritis, diabetes, atherosclerosis, Alzheimer's disease, inflammatory bowel disease, ischemia/reperfusion injury, sepsis, and hemophagocytic lymphohistiocytosis. These insights establish an interdisciplinary design framework for developing clinically applicable ICTAs and propose novel therapeutic approaches for inflammation-related diseases.

Targeting cancer-associated fibroblast-activated HGF/c-MET pathway inhibits extrahepatic cholangiocarcinoma progression and restores gemcitabine therapeutic sensitivity

Mingzhen Bai, Ping Yue, Wenkang Fu, Ruyang Zhong, Chongfei Huang, Ningzu Jiang, Long Gao, Ningning Mi, Haidong Ma, Yawen Lu, Liang Tian, Jinyu Zhao, Ziang Zhang, Yong Zhang, Jinduo Zhang, Yanxian Ren, Haiying Yu, Jia Yao, Dewei Li, Yanyan Lin, Wenbo Meng

Acta Pharmaceutica Sinica B. 2026, 16(5): 3074-3089.

Cholangiocarcinoma (CCA) is a markedly desmoplastic tumor, with extrahepatic CCA (eCCA) being the most prevalent subtype. The nonspecific clinical manifestation and early metastatic potential result in a persistently poor overall prognosis. Cancer-associated fibroblasts (CAFs) are one of the major components of the tumor microenvironment implicated in tumor progression and treatment resistance. To faithfully recapitulate the eCCA microenvironment, we established a comprehensive patient-derived preclinical platform comprising CAFs, eCCA primary cells, organoids, and patient-derived xenograft (PDX) models. We found that CAFs facilitated eCCA cell growth, migration, and invasion in vivo and in vitro. Cytokine profiling revealed that HGF is a key paracrine factor produced by CAFs. CAF-derived HGF activates c-MET signaling to drive gemcitabine resistance in eCCA. Therapeutically, pharmacologic inhibition of c-MET partially resensitized eCCA cells to gemcitabine in preclinical models and suppressed tumor progression. In conclusion, our data provides subtype-specific translational evidence that therapeutically targeting the CAF-HGF-c-MET pathway represents a rational strategy to enhance gemcitabine efficacy and improve treatment outcomes in eCCA.

Author correction to “Triterpenoids-templated self-assembly nanosystem for biomimetic delivery of CRISPR/Cas9 based on the synergy of TLR-2 and ICB to enhance HCC immunotherapy” [Acta Pharm Sin B 14 (2024) 3205-3217]

Acta Pharmaceutica Sinica B. 2026, 16(5): 3254-3255.