Acta Pharmaceutica Sinica B

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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.
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.
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.
Microneedle technology integrated with diverse therapeutic modalities for hair regrowth in alopecia

Acta Pharmaceutica Sinica B. 2026, 16(6): 3400-3424.

Alopecia profoundly impacts an individual’s appearance, quality of life, and social well-being, with its prevalence increasing with age. Conventional treatments, such as topical minoxidil and oral finasteride, suffer from limitations like inefficient drug delivery, side effects, and inconsistent efficacy. Other therapies, like hair transplantation, biologics and low-level laser therapy (LLLT), also face some constraints in practical application. Microneedles (MNs), as an emerging transdermal drug delivery system (TDDS), enable efficient local delivery of therapeutic agents to hair follicles in the balding scalp by physically penetrate stratum corneum. Through enhanced drug permeability and activation of follicular regeneration pathways, MN-combined strategies have ignited considerable research interest. This review outlines the advances in MN-mediated alopecia treatments over the past five years and underscores their potential to enhance hair regrowth efficacy, including MN-assisted delivery of chemical drugs, natural compounds, biologics, nanomedicines, stem cells, and LLLT. Additionally, this review also summarizes the advances in clinical trials of MN-combined therapies for alopecia over the past five years, highlighting the noticeable disconnection in research focus between basic research and clinical trials. In summary, this review aims to provide critical insights and future perspectives for the development of MN-integrated therapies for alopecia management.
Smart responsive hydrogels combined with AI design for tumor therapy

Acta Pharmaceutica Sinica B. 2026, 16(6): 3425-3472.

Advances in cancer therapy have underscored the critical need for multifunctional platforms that enable precise targeting, controlled drug release, and immunomodulation. Hydrogels, as transformative tools with programmable drug release capabilities, microenvironmental responsiveness, and immunoregulatory properties, demonstrate broad application prospects. This review focuses on the design and application of functionalized hydrogels, emphasizing their responsiveness to multiple stimuli, including temperature, pH, reactive oxygen species (ROS), and enzymes. It provides an in-depth analysis of their multimodal synergistic therapeutic mechanisms, including photothermal therapy, immunotherapy, starvation therapy, intelligent detection, targeted capture, and tumor microenvironment (TME) simulation. Meanwhile, recent developments in machine learning-enabled intelligent hydrogel technologies have driven the transformation of materials into intelligent systems with “smart design-perception-decision” capabilities. Although the literature on smart hydrogels has made significant progress in exploring mechanisms and optimizing performance, systematic reviews of artificial intelligence (AI)-driven platforms remain notably lacking. This paper systematically summarizes the regulatory strategies of material-derived intelligent hydrogels, AI-enabled mechanisms, and practical application cases, revealing core challenges and future development directions, thereby providing theoretical guidance and practical pathways for next-generation hydrogels in personalized and multimodal cancer therapy.
Advanced drug delivery platforms targeting cellular senescence: A promising strategy for cancer therapy

Acta Pharmaceutica Sinica B. 2026, 16(6): 3473-3505.

Cellular senescence is a state of cell cycle arrest caused by various types of stress, and it is characterized by morphological changes, metabolic reprogramming, and the release of the senescence-associated secretory phenotype (SASP). In cancer therapy, senescence plays a complex role by inhibiting cancer progression, mediating metabolic imbalance, modulating local immune responses, and restructuring the cancer microenvironment. These mechanisms have been harnessed to develop nano-drug delivery systems (Nano-DDSs)-based combination therapies for cancer. We systematically explain key biological features of cellular senescence and detail recent advances in creating drug delivery systems aimed at targeting cancer senescence through these four mechanisms. Additionally, we discuss the clinical challenges in translating senescence-targeting strategies with Nano-DDSs and propose future directions within an interdisciplinary framework. This review offers valuable insights into designing advanced Nano-DDSs based on the multidimensional regulatory mechanisms of cellular senescence and their application in cancer treatment.
Engineered cell-biomimetic nanosystems for anti-inflammatory therapy: Targeting, neutralization and immunomodulation

Acta Pharmaceutica Sinica B. 2026, 16(6): 3506-3539.

Inflammation is a complex and dynamic immune response triggered by tissue injury or pathogen invasion, playing a critical role in restoring tissue homeostasis. However, excessive inflammation can lead to tissue damage and exacerbate the progression of various diseases. Issues such as off-target effects and insufficient dynamic regulation pose key challenges to precise modulation of complex inflammatory processes, thereby enhancing efficacy while minimizing adverse effects. Engineered cell-biomimetic nanosystems (ECNs), including membrane-coated nanoparticles, extracellular vesicles (ECVs), and cell-nanoparticle hybrids, are highly adaptable biomimetic platforms with tunable physicochemical properties. Beyond carrier functions, ECNs are capable of actively responding to inflammation-related targets and interacting with the immune microenvironment, thereby promoting the dynamic regulation of inflammation. This review summarizes recent advances in ECNs, with an emphasis on targeting mechanisms and key strategies for inflammatory intervention. These include precise targeting of inflamed tissues, biological neutralization of toxins and overexpressed inflammatory factors to interrupt the inflammatory cascade, and immunomodulatory functions that balance immune responses to achieve activation or suppression. Physical, chemical, and biological engineering strategies for modifying cells and cell membranes for inflammation targeting are also discussed. As an emerging platform for targeted drug delivery and immune regulation, ECNs provide innovative technological approaches for inflammation therapy.
Engineered extracellular vesicles for combinatorial cancer therapy and imaging

Anita S. La'ah, Nashmin Fayazi Hosseini, Choongmo Kang, Amirhossein Ahmadieh-Yazdi, Mohsen Sheykhhasan, Piao Yang, Armita Ghotaslou, Hamed Manoochehri, Yun Suk Huh, Heemin Kang, Pooyan Makvandi

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.
The mechanisms and strategies for Alzheimer’s disease prevention: An update

Acta Pharmaceutica Sinica B. 2026, 16(6): 3582-3602.

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, poses growing global health and socioeconomic challenges due to aging populations and limited therapeutic efficacy. Current treatments, including cholinesterase inhibitors and anti-amyloid monoclonal antibodies, can only delay disease progression without reversing pathology. Emphasizing on prevention, this review provides key updates on advancements in the pathogenesis, diagnosis, and intervention of AD highlighting preventive strategies that can target modifiable risk factors. Key findings underscore the role of managing hypertension and diabetes, optimizing trace elements, vitamins, and regular physical exercise in mitigating the risk of AD. Biomarker-based early diagnosis and emerging therapies provide further support for proactive intervention. Future challenges include the long-term validation of preventive measures and policy-driven funding for large-scale cohort studies. Prioritizing prevention through lifestyle modifications, nutritional balance, and precision medicine is pivotal to reduce the burden of AD in aging societies.

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