Acta Pharmaceutica Sinica B

Universal off-the-shelf TGF-β1-knockout whole-tumor cell vaccine overcomes immunotherapy resistance in pMMR/MSS tumors

Weixiao Yang, Zhexu Dong, Qi Xiong, Yushuang Ren, Lin Zhang, Yi Liu, Jiaqi Han, Tian Tian, Xiaolan Su, Gang Shi, Hongxin Deng

Acta Pharmaceutica Sinica B. 2026, 16(8): 5405-5423.

Mismatch repair-proficient (pMMR)/microsatellite-stable (MSS) tumors, representing the majority of solid cancers, remain largely unresponsive to immune checkpoint inhibitors, highlighting the urgent need for effective therapeutic strategies. Tumor cell vaccines, serving as delivery platforms for a broad repertoire of tumor antigens, hold potential for eliciting systemic antitumor immunity, yet their clinical efficacy has remained limited. Here, we developed Tβ1KO/PolyIC-Vac, an off-the-shelf therapeutic whole-tumor cell vaccine generated by CRISPR-Cas9-mediated TGF-β1 knockout and formulated with the TLR3 agonist Poly(I:C). In therapeutic vaccination models, subcutaneous vaccination significantly suppressed distal tumor growth, reduced lung metastases, and delayed spontaneous colorectal tumor progression. It also synergized with anti-PD-1 blockade, enhancing complete response rates and establishing baseline antitumor immunity. Mechanistically, knockout of tumor-derived TGF-β1 reprogrammed immunity by reducing MDSC accumulation to relieve local immunosuppression and activate dendritic cells in draining lymph nodes, while intrinsically triggering the tumor STAT1-IL-15 axis to enhance vaccine immunogenicity. Poly(I:C) further enhanced cross-presentation and adaptive immunity, conferring long-term cross-protection against heterologous tumors. Together, these findings establish Tβ1KO/PolyIC-Vac as a universal tumor vaccine platform capable of efficiently delivering a comprehensive repertoire of tumor antigens and eliciting robust, durable, and cross-protective tumor-specific immunity in immunotherapy-resistant pMMR/MSS tumors.

IFI30 reprograms glioblastoma-associated macrophage and induces immune evasion by MAFF/PTGS2 pathway

Sen Zhang, Wenlin Chen, Liwen Ren, Jie Yi, Xiangjin Zheng, Yihui Yang, Hong Yang, Guanhua Du, Wan Li, Yu Wang, Jinhua Wang

Acta Pharmaceutica Sinica B. 2026, 16(8): 5297-5311.

In recent years, immunotherapy has shown obvious advantages in treating cancers. The close interaction between cancer cells and immune cells in the tumor microenvironment (TME) underlies the progression of glioblastoma multiforme (GBM). However, there are no effective immune-related targets against GBM. Here, in silico analyses and experimental data showed that Interferon Gamma Inducible Protein 30 (IFI30), modulated by histone modifications both H3K4me3 and H3K27ac, was up-regulated in GBM and had a potential role in the antitumor immune responses. In vitro and in vivo experiments further revealed that IFI30 modulated the infiltration of tumor-associated macrophages (TAMs) and reduced the proportion of CD8⁺ T cells. Mechanistically, IFI30 induced PGE2 expression in GBM cells via the MAFF/PTGS2 pathway, and PGE2 bound to macrophage EP2/EP4, activating the downstream ERK1/2 and KLF4/STAT6 pathways, stimulating the infiltration of TAMs. Taken together, we characterized the role and mechanisms of IFI30 in the malignant progression of GBM by regulating TAMs, highlighting that IFI30 may benefit GBM patients as a therapeutic target.

Optimizing pyrazine-2-carboxamide derivatives as dual FLT3/HDAC inhibitors with enhanced pharmacokinetics and immunotherapeutic potential

Yingjie Chang, Xue Li, Huirui Wang, Huajun Zhao, Yue Zhou, Wenchao Bi, Ruixue Cheng, Yuxin Shi, He Weng, Xinying Yang, Wei Zhao, Hao Fang, Xuben Hou

Acta Pharmaceutica Sinica B. 2026, 16(8): 5383-5404.

Dual FLT3/HDAC inhibition represents a promising synergistic strategy to address tumor heterogeneity. Building upon our prior lead 25h, we developed novel 6-ethylpyrazine-2-carboxamide derivatives via systematic structural optimization to enhance pharmacokinetic properties and target selectivity. The optimized compound, CF-2-17, demonstrated potent dual inhibition of FLT3 (IC₅₀ = 1.1 nmol/L) and HDACs (IC₅₀ = 9.6 nmol/L), and exhibited a 27-fold selectivity for HDAC1 over HDAC6. Its improved physicochemical properties, including enhanced solubility and metabolic stability, translated into favorable plasma exposure in vivo. In the MOLM-13 (FLT3-ITD) xenograft model, oral administration of CF-2-17 showed antitumor efficacy comparable to combination therapy, without observable toxicity. CF-2-17 also exhibited antiproliferative activity against non-FLT3-ITD hematological malignancies and solid tumors, outperforming single-target agents. Furthermore, CF-2-17 effectively remodeled the tumor immune microenvironment through CD4⁺ T cell activation and IFN-γ elevation, achieving 87% tumor growth inhibition in LLC syngeneic models. Mechanistically, CF-2-17 reversed FLT3 blockade-induced DC dysfunction via activation of the NF-κB pathway, thereby reinstating DC-mediated antitumor immunity. This dual FLT3/HDAC inhibitor demonstrates synergistic epigenetic-immune modulation, offering a promising approach for heterogeneous malignancies.

Progranulin drives acetaminophen-induced acute liver injury by limiting hepatic recruitment of eosinophils via suppressing interleukin-33 expression

Yin Tang, Siyuan Xie, Yueyue He, Jiayu Liu, Mingang Pan, Renlin Yu, Linghong Zhou, Mengxue Liu, Yi Liu, Ju Cao

Acta Pharmaceutica Sinica B. 2026, 16(8): 5086-5107.

Drug-induced liver injury (DILI), particularly acetaminophen (APAP)-induced acute liver injury (ALI), is the leading cause of acute liver failure. Progranulin (PGRN) is a multifunctional glycoprotein. However, the role of PGRN in APAP-induced ALI remains unknown. Here, we found that PGRN serum concentration increased and correlated with disease severity in the patients with APAP overdose. Mice with PGRN deficiency were protected from APAP-induced ALI or concanavalin A (ConA)-induced ALI. They exhibited substantially increased hepatic recruitment of eosinophils, which depended on up-regulated IL-33 that was primarily released from liver sinusoidal endothelial cells (LSECs). Moreover, treatment of mice with blocking PGRN antibody could prophylactically and therapeutically treat APAP- or ConA-induced ALI, while injection of recombinant PGRN protein enhanced APAP-induced liver damage and worsened survival. Mechanistically, PGRN inhibited APAP-induced IL-33 expression in LSECs by dampening the activation of AMP-activated protein kinase (AMPK)-forkhead box O3 (FOXO3) signaling pathway. Therefore, PGRN should be considered as a new biomarker and potential therapeutic target to treat DILI.

Design, preclinical evaluation, and multicenter phase 1 clinical study of HZ-A-018 for relapsed or refractory central nervous system lymphoma

Acta Pharmaceutica Sinica B. 2026, 16(8): 5351-5362.

Effective therapy for relapsed or refractory central nervous system lymphoma (r/r CNSL) remains an unmet medical need. Meanwhile, developing antitumor drugs for CNS malignancies faces the dual challenge of achieving effective blood‒brain barrier (BBB) penetration and potent tumor cell killing. To address these challenges, a comprehensive predictive system was established to support decision-making during the discovery of HZ-A-018, a potent and BBB-permeable Bruton tyrosine kinase (BTK) inhibitor. This study further presents key preclinical results for HZ-A-018, as well as efficacy/safety data from a multicenter Phase 1 trial in r/r CNSL patients. HZ-A-018 demonstrated manageable safety, with only 19.2% of patients experienced grade 3 or higher adverse events according to the Common Terminology Criteria for Adverse Events version 5.0. Treatment with HZ-A-018 at the recommended phase II dose (RP2D) of 600 mg achieved an overall response rate (ORR) of 72.7% (95% CI, 39.0-94.0) and a 12-month survival rate of 90.5%. The Center for Drug Evaluation in China has authorized the initiation of this single-arm Phase II study as a pivotal registrational clinical trial for accelerated approval of HZ-A-018 for monotherapy in patients with r/r PCNSL. This trial has been registered under the identifiers ChiCTR2400091821 at www.chictr.org.cn and CTR20210181 at www.chinadrugtrials.org.cn.

A destination-driven framework for nanoparticle-enabled targeted protein degradation

Acta Pharmaceutica Sinica B. 2026, 16(8): 4854-4875.

Targeted protein degradation (TPD) offers a revolutionary paradigm to eliminate disease-driving proteins. Given the distinct technical requirements and challenges associated with degrading intracellular versus extracellular proteins, we classify existing TPD strategies based on subcellular localization into two categories: intracellular TPD (iTPD), which targets proteins within the cytoplasm and nucleus, and extracellular TPD (eTPD), which focuses on membrane-bound and secreted proteins. This destination-based framework facilitates precise technology selection and rational design by aligning methods with the biological context of their targets. However, the clinical translation of TPD remains constrained by a significant “delivery gap”. Current nanotechnological approaches are often discussed monolithically, despite the fundamentally distinct delivery requirements between iTPD and eTPD. For iTPD, the primary nanocarrier role is to confer fundamental drug-like properties to overcome systemic pharmacokinetic hurdles. Conversely, for eTPD, the nanoplatform's chief function is to engineer cellular engagement, enhance internalization, and orchestrate correct intracellular trafficking to the lysosome. This review will dissect the distinct challenges inherent to each “geographic” space and detail the tailored nano-playbooks being developed to address them. We will further explore the convergence of these two worlds and the emergence of nanoparticles as intrinsic degraders. Ultimately, we argue that a location-aware design philosophy is essential for unlocking the full therapeutic potential of TPD.

Targeting NAT10 with Remodelin reshapes the pro-fibrotic microenvironment in renal fibrogenesis via inhibiting exosome oversecretion from tubular cells

Yuqin Tan, Jiaojiao Zheng, Ruojiao Wang, Zhaozhong Zhong, Suxiang Chen, Shuo Lu, Jiayu Zheng, Yongrong Ye, Ning Na, Tong Zheng

Acta Pharmaceutica Sinica B. 2026, 16(8): 5328-5350.

Renal fibrosis induces irreversible renal failure and lacks therapies. The tubular epithelial cells (TEC) largely depend on exosomes to create a pro-fibrotic microenvironment, initiating fibroblast activation. However, how exosome secretion of TEC is over-activated during renal fibrogenesis remains unknown. Herein, in vitro high-throughout screen uncovered acetyltransferase NAT10 as promising target to interfere with TEC-fibroblast communication. Further experiments showed that NAT10 was upregulated mainly in the TEC of fibrotic kidneys, and its conditional depletion in TEC alleviated renal fibrosis in vivo. Mechanistically, nuclear NAT10 coordinated with cytoplasmic NAT10 to promote exosome secretion of TEC to induce fibroblast activation via combining mRNA ac4C modification and lysine acetylation (Kac). Moreover, NAT10 upregulated the abundance of exosomal Gli in TEC, which were vital for fibroblast activation. In summary, NAT10-mediated orchestration of ac4C and Kac modifications is the mechanism of over-activated exosome secretion of TEC during renal fibrogenesis. And targeting NAT10 with Remodelin is a promising therapy for renal.

H2AC19 promotes lung adenocarcinoma progression via p300/EGR1/MMP-1-mediated angiogenesis

Fuwen Zuo, Jinlong Yu, Tong Liu, Xiaorui Liu, Jilong Yin, Pengzhong Ding, Yuhan Pang, Zhengdong Luo, Xiaofeng Wang, Ling Guo, Yirong Zhang, Shuang Qi, Lutao Du, Ziying Wang, Fan Yi, Xiaoshi Zhang

Acta Pharmaceutica Sinica B. 2026, 16(8): 5070-5085.

Angiogenesis is a hallmark of lung adenocarcinoma (LUAD) and a leading cause of mortality. Identifying potential therapeutic targets that modulate this process is of critical clinical importance. Here, we established a 12-gene risk-scoring model through bioinformatics screening and systematically delineated the molecular function of H2AC19, a previously poorly understood histone variant within this signature. Analysis of human LUAD specimens revealed elevated H2AC19 expression, which correlated positively with angiogenesis markers and advanced clinical stage and negatively with patient prognosis. Functional validation using CRISPR/Cas9 in patient-derived organoids (PDOs), in vitro cell models and in vivo xenografts demonstrated that H2AC19 promotes angiogenesis and tumor growth. Mechanistically, H2AC19 recruits p300 through its amino acid residues 24-88 to specifically augment H3K27 acetylation at the EGR1 promoter region, thereby triggering EGR1 transcriptional activation and subsequently promoting MMP-1-driven angiogenesis and progression of LUAD. Furthermore, we evaluated the therapeutic potential of lipid nanoparticles (LNP)-encapsulated siRNA targeting H2AC19, which significantly suppressed angiogenesis and LUAD progression. Collectively, our findings establish a critical role for H2AC19 in governing angiogenesis and highlight its potential as a promising therapeutic target for LUAD.

Phase change nanodroplets: Challenges and clinical potential

Acta Pharmaceutica Sinica B. 2026, 16(8): 4998-5015.

Phase change nanodroplets (PCND) consist of a liquid fluorocarbon core, which vaporizes into gas upon energy excitation, and a stabilizing shell. Through this phase-change property, PCND combine nanoparticle-like stability and pharmacokinetics, such as tissue extravasation and uptake by the mononuclear phagocyte system, with distinctive microbubble-like capabilities, namely ultrasound contrast enhancement and energy-triggered therapeutic action. PCND serve both as highly sensitive imaging agents, from molecular imaging to high-resolution vascular mapping, and as versatile therapeutics, used for example for thrombolysis, tissue ablation, biofilm removal, immunomodulation, and drug delivery. This review article provides a focused review of the biological behavior of PCND, including blood half-life, biodistribution, clearance pathways, and tumor accumulation, following a brief overview of the key physicochemical features that shape their in vivo fate. By comparing data across studies, we identify major inconsistencies in reported pharmacokinetics and highlight critical knowledge gaps, particularly regarding safety data. We further summarize advances in PCND-enabled imaging and therapy, and propose strategies to strengthen formulation design, biological evaluation, and stimulation protocols to support future clinical translation. Overall, PCND hold strong potential as a versatile theranostic platform. Continued systematic and clinically focused research is expected to accelerate their path toward clinical translation.

A novel machine learning framework-based rapid screening of ionizable lipids in LNPs for highly-efficient mRNA expression

Acta Pharmaceutica Sinica B. 2026, 16(8): 5053-5069.

Ionizable lipids are a pivotal component for lipid nanoparticles (LNPs) to optimize mRNA expression to fulfill the broad demands of various mRNA therapeutics. Traditionally, the screening of ionizable lipids needs extensive synthetic labor and stringent in vivo efficacy evaluation, which was often time-consuming, costly, and characterized by a lower success rate. Hence, we pioneered a machine-learning framework named Lipid with Artificial Intelligence (LipidAI) to evaluate the novel ionizable lipids rapidly. In this framework, the Methyl Tail Augmentation (MTA) strategy was first developed to triple the data by precisely adjusting the methyl groups on lipid tail chains. This ground-breaking approach compensated for data paucity in ionizable lipids libraries from the previous research and boosts model accuracy. Subsequently, the Ensemble Stacking Learning (ESL) algorithm was exploited to integrate multiple learning algorithms to surpass the predictive accuracy of a single algorithm used in former studies. Finally, we found that the predicted results of LipidAI were highly consistent with the actual data according to the in vivo expression of Luc-mRNA. Overall, this study highlights the remarkable potential of LipidAI in the rapid screening of ionizable lipids, adeptly avoiding the inherent drawbacks of traditional ionizable lipids development and thereby boosting the progress of LNP-based mRNA nano-drugs.