This week, several studies have made key breakthroughs in tumor immunology, regenerative medicine, and drug resistance mechanisms: a team from Peking Union Medical College successfully reversed prostate cancer immunotherapy resistance using mRNA 3’UTR engineering; Sun Yat-sen University revealed that targeting DTP cells can delay EGFR-TKI resistance. Meanwhile, Guangzhou National Laboratory has established high-fidelity multi-level branched lung organoids, providing a new model for lung regeneration research. In addition, the Sichuan University team discovered a new “liver-gut” communication mechanism regulating blood glucose in fatty liver. Fudan University and Nanjing Medical University have made significant progress in the chronic pain-depression comorbidity circuit and stem cell transplant immune rejection research, opening new pathways for related disease treatment.

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1. The Peking Union Medical College team uses mRNA 3’UTR engineering to overcome resistance to prostate cancer immunotherapy

On June 16, the original breakthrough results of Wang Qianben’s team from Peking Union Medical College were published online in Nature Biomedical Engineering, addressing the core bottlenecks in immunocold tumor clinical treatment. This fills a gap in the global gap where no approved therapy can effectively restore tumor MHC-I antigen presentation.
Currently, immuno-cold tumors represented by castration-resistant prostate cancer have a clinical response rate of less than 12% for PD-1/PD-L1 immune checkpoint inhibitors. The core trigger is impaired antigen presentation via the MHC-I pathway in tumor cells, and previous studies have not identified precise intervention targets. This study identified mRNA 3′-terminus variable polyadenylation (APA), a post-transcriptional regulatory abnormality, as a novel targeted immune escape mechanism: the team compared transcripts between clinical prostate cancer samples and normal prostate tissue by comparing multi-omics and the differences in transcripts, and found that the tumor-specific 3′ UTR of the SPSB1 gene is abnormally shortened, which removes endogenous negative regulatory elements from its transcripts, resulting in abnormally high expression of SPSB1 E3 ubiquitin ligase. It directly mediates ubiquitinated degradation of the MHC-I heavy chain, ultimately completely blocking the tumor antigen presentation process.

Based on this mechanism, the team independently built the world’s first programmable 3’UTR correction RNA engineering platform, 3’UTRCES, combined with a clinically proven safe lipid nanoparticle (LNP) delivery system, enabling precise reversal of abnormal APA events within tumor cells without editing the host genome. Validation of the in situ prostate cancer model shows that after intervention, intratumoral MHC-I expression levels have recovered to over 80% of normal epithelial cells. Tumors that were previously completely resistant to immunotherapy have regained sensitivity to PD-1 inhibitors. This platform is cross-tumor universal, opening a new development path for post-transcriptional RNA engineering.

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2. Sun Yat-sen University reveals new mechanisms targeting DTP cells to delay EGFR-TKI resistance and combined prevention strategies

On June 18, Professor Fang Wenfeng’s research group at Sun Yat-sen University published a groundbreaking original study in the top oncology journal Cancer Cell, systematically analyzing for the first time the key regulatory mechanisms of drug-tolerant persistent cells (DTPs, i.e., residual “resistance seeds” after EGFR-TKI treatment) in EGFR-mutant non-small cell lung cancer (NSCLC), providing a high-value combined prevention and treatment pathway for clinical resistance of third-generation EGFR-TKIs.
Current clinical data show that the initial response rate of EGFR-TKI monotherapy can exceed 70%, but nearly half of patients develop acquired resistance within 1~2 years, and the long-term retention of DTP cells is the core cause of resistance and tumor recurrence. The research team verified through dynamic transcriptome tracking that the targeted signaling inhibitory effect of EGFR-TKI can specifically neutralize the transcriptional inhibition of the protooncogene c-Myc on the transmembrane target TROP2, driving significant upregulation of TROP2 on the surface of DTP cell membranes. Moreover, TROP2 expression directly supports the maintenance of the stem cell-like phenotype and long-term survival of DTP cells, ultimately confirming that TROP2 is a novel, druggable fragile site in DTP cells that has not been discovered before.

Based on this mechanistic insight, the research team explored combining the TROP2-targeted antibody conjugate drug (ADC) sac-TMT with osimertinib. A series of preclinical model results show that this combination can completely inhibit DTP cell formation and significantly delay tumor recurrence. Simultaneously published preliminary phase 2 clinical data also confirm that this combination regimen is significantly more effective as first-line treatment for advanced EGFR-mutated NSCLC than existing monotherapy standard therapies, providing solid theoretical and evidence-based support for subsequent paradigm innovations in first-line treatment.

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3. Dev Cell: Guangzhou National Laboratory and others collaborate to build multi-level branched lung organoids

 On June 18, Cao Shangtao’s team at Guangzhou National Laboratory, together with several research institutions, published a major original report in the top developmental biology journal Developmental CellSuccessfully constructed a high-fidelity multilevel branched lung organoid (BLO), filling a long-term model gap in lung development and regeneration research.

For a long time, traditional in vitro lung organoids have faced industry pain points such as structural simplification and incomplete lineage specialization, which can only form irregular simple cystic structures and cannot reproduce the dendritic multilevel branching layout of lung epithelium or the specialized features of near and distal functional zones, greatly limiting the efficiency of analyzing lung morphogenetic mechanisms, screening new drugs for respiratory diseases, and validating cell replacement therapies.

In this study, the team optimized stem cell-induced microenvironment and biomechanical regulation schemes, enabling BLOs to autonomously complete the entire in vivo lung development process in vitro: through single-cell transcriptome sequencing and long-duration live cell imaging cross-validation, the model not only fully reproduced the dendritic branching structure of the physiological lung, the specialized features of proximal airway and distal alveolar functional zones, but also spontaneously formed alveolar sac-like structures with gas exchange unit properties, whose branches emerge from buds, The extended dynamic timing patterns closely align with the development of the embryonic lung in vivo. Transplantation experiments further confirmed that functional epithelial cells derived from BLO can mature and integrate in targeted areas of damaged lung microenvironments, effectively alleviating the progression of pulmonary fibrosis in model animals. This platform provides a brand-new core tool for studying lung development mechanisms and developing regenerative therapies for refractory interstitial lung diseases.

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4. A false alarm! Virus detected after HIV treatment? It turns out it is not infectious or pathogenic

Currently, over 28 million people worldwide are receiving standard antiretroviral therapy (ART). Long-term virological suppression is the core treatment goal, but 7%-18% of those who receive long-term standard treatment experience persistent or intermittent low-level viral detection, known as “non-suppressive viremia,” which has long been a clinical concern. Previously, the industry generally regarded this phenomenon as a warning sign of viral breakthroughs and the emergence of resistance, often initiating unnecessary resistance testing and adjusting intensive treatment plans, which not only increased medical costs but also caused severe psychological anxiety and stigma among patients.

Recently, a cohort study conducted by Johns Hopkins University School of Medicine in collaboration with multiple institutions has reached a groundbreaking conclusion: this type of residual virus is almost completely incapable of infecting and causing pathogens. The study included a cohort of 52 infected individuals who had received ART for over 3 years, had no history of resistance mutations, and whose viral load fluctuated long-term between 20-1000 copies/mL. Using the independently developed CLAWS full-length proviral targeted sequencing technology, over 95% of HIV-1 in plasma was confirmed RNA comes from defective protoviruses with 5′ progenitor region mutations or large deletions, making it impossible to assemble intact viral particles with infectious properties, which neither drives disease progression nor poses a risk of human-to-human transmission.

The study also confirmed that these defective viral genomes began to dominate the residual virus database within six months after ART was initiated, with subsequent detected traces of viruses being “virus fragments” without replication capability. This achievement not only directly reduces the annual unnecessary medical expenses of nearly 1,000 yuan for related patients, but also provides a new reference dimension for the endpoint evaluation system for HIV functional cure. Currently, CLAWS testing technology is advancing clinical standardization, and will later be validated across larger cohorts of infected individuals.

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5. Sichuan University Team Reveals New Mechanism

for Fatty Liver Regulating Glycemic Homeostasis via “Liver-Gut” Communication On June 17, the latest original findings from the team led by Chen Haiyang and Chen Yi from Sichuan University were published online, explaining for the first time the novel mechanism by which non-alcoholic fatty liver regulates glycemic homeostasis via remote “liver-gut” communication. This breaks the traditional belief in the field that fatty liver-driven hyperglycemia relies solely on intrahepatic gluconeogenesis pathways.

Currently, the global prevalence of non-alcoholic fatty liver disease has surpassed 30%. Clinical epidemiological data show that the risk of developing type 2 diabetes in people with fatty liver is more than twice that of healthy individuals. However, the core link of how pathological changes in the liver remotely affect systemic glucose metabolism has long remained unclear. This study is the first to confirm that alkaline phosphatase (ALP) synthesized and secreted by hepatocytes under the fatty liver microenvironment can target α2δ-1 receptors on the surface of intestinal stem cells (ISCs) via the circulatory system, inducing translocation of the L-type calcium channel Cav1.2 membrane, triggering upregulation of intracellular calcium signaling and activating the calcineurin phosphatase/NFATC2 axis, inhibiting the expression of SOX21, a key regulator of ISC differentiation, and downregulating downstream levels of bone morphogenetic protein 7. Specifically, ISCs inhibit the directed differentiation of ISCs into intestinal L cells that secrete glycemic peptides such as GLP-1, directly leading to atrophy of the enterogenic endocrine hormone pool. This pathogenic process is completely independent of the enhanced intrahepatic gluconeogenesis pathway.Preclinical efficacy validation shows that targeting the inhibition of fatty liver-related ALP synthesis can independently exert a hypoglycemic effect and synergistically enhance metformin’s hypoglycemic efficacy, providing a novel intervention target for patients with fatty liver combined with type 2 diabetes and opening new directions for cross-organ communication research on metabolic diseases.

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6. Fudan University Reveals New Neural Circuit Mechanisms

for Chronic Pain and Depression Comorbidity On June 11, the team led by Zhang Yuqiu and Liu Benlong from the Fudan University Institute of Brain Science published their major findings on new neural circuits for chronic pain-depression comorbidities in the top neuroscience journal Neuron. , providing a brand-new, precise intervention pathway for long-standing unmet clinical treatment needs for comorbidities.

According to global epidemiological statistics, about 22% of chronic neuropathological pain patients also have moderate to severe anxiety and depression comorbidities. Current nonsteroidal and opioid analgesics can only partially alleviate somatic pain symptoms, but the response rate for comorbid mood disorders is less than 27%. Long-term drug tolerance and addiction risks further increase the clinical treatment burden. Previous research has confirmed that the mesolimbic dopamine circuit is the core carrier for the interaction regulation of pain and negative emotions, but the specific projection subgroups and receptor functional division have never been clearly resolved, becoming a key obstacle to targeted new drug development.

In this study, the team used retroviral tracing and optogenetic manipulation combined with in vivo calcium signal recording, and for the first time confirmed that neuropathological pain can specifically induce persistent hypodopaminergic states in the ventral tegmental area–orbitofrontal cortex (VTA-OFC) projection pathway. Precisely activating this pathway can simultaneously reverse hypersensitivity to pain and depressive-like behaviors in model mice, with two completely independent effects: Among them, D1-positive neurons in the orbitofrontal cortex specifically mediate the alleviation of anxiety-depressive comorbidities, while D2-positive neurons independently regulate the improvement of abnormal pain sensation.

This achievement is the first to achieve precise circuit-level decomposition of two core symptoms of chronic pain, providing a solid anatomical basis for non-addictive precision analgesic drugs targeting subtypes and personalized deep brain stimulation protocols. The related translational pipeline has initiated preclinical validation, promising to fill the clinical gap where existing treatments cannot simultaneously cover multiple symptoms.

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7. The Guangzhou Medical University team discovered a new target for treating Crohn’s disease fibrosis, WNT2B

In response to the urgent unmet need for clinical antifibrotic treatment for Crohn’s disease (CD)—the recurrence rate of intestinal stricture within five years after surgery in patients with moderate to severe CD exceeds 50%, and existing biologics such as TNF-α have less than 30% response rates to established organic fibrotic lesions. Globally, no specific antifibrotic targeted drugs have been approved. Recently, Cheng Yang’s team at Guangzhou Medical University published an original study in the top autophagy journal AutophagyFor the first time, WNT2B was established as a novel therapeutic target for CD and autophagy-related fibrosis diseases, filling a long-term research gap in intracellular non-classical WNT functional regulation in this field.
This achievement breaks through the traditional academic understanding that WNT2B is only a paracrine signaling ligand, revealing its pathological non-secretory intracellular function for the first time: WNT2B with high accumulation in fibrotic lesions can directly bind to the WASH complex core subunit WASHC5, disrupting the assembly of the complete functional complex. By inhibiting early actin polymerization mediated by ARP2/3 on the endosomal surface, it blocks the sorting and transportation of endosomal goods, directly causing functional defects during the autophagy initiation stage , driving the enrichment of pro-inflammatory and pro-fibrotic effector factors in fibroblasts in the intestinal layer of propria.
Animal experiments confirmed that fibroblast-specific knockout of Wnt2b in CD model mice had a 73% recovery rate of intestinal autophagy flux, a 62% reduction in collagen deposition area, and no tumor risk associated with systemic Wnt pathway activation. Cohort analysis based on 127 clinical surgical samples from CD showed that intracellular WNT2B expression in fibrotic areas was significantly negatively correlated with patient autophagy activity, and positively correlated with stenosis recurrence rate and disease severity. The newly identified LC3B-II-dependent WNT2B autophagy secretion pathway also provides a completely differentiated new intervention entry point for subsequent first-in-class anti-fibrotic small molecule development.

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8. Zhao Lihua / Xu Huaqiang’s team elucidates the molecular mechanism

of LPA recognition by LPAR5 On June 18, Zhao Lihua’s team at Ruijin Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, together with Xu Huaqiang’s team from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, published a report in the top international academic journal The Proceedings of the National Academy of Sciences (PNAS) published a groundbreaking original achievement, for the first time using a high-resolution cryo-EM structure of 2.96Å to resolve the atomic conformation of the hemolytic phospholiphatidic acid receptor 5 (LPAR5)-endogenous agonist 1-oleacyl-LPA-Gq protein ternary complex, filling a signal transduction mechanism gap for this high-potential drug target.

Hemolytic phospholipid acid (LPA) is a core lipid signaling molecule regulating cell proliferation, migration, and inflammatory responses. It mediates a wide range of physiological and pathological effects through six Class A GPCR subtypes. Among them, LPAR5 is a core candidate in neuropathic pain, organ fibrosis, and tumor metastasis, but its ligand recognition pattern and the molecular basis of G protein coupling have long been unclear. This greatly restricts the development progress of subtype selective new drugs.

This study is the first to confirm that 1-oleoyl-LPA binds to the orthostructured pocket of LPAR5 in a typical amphiphilic pattern: the polar head phosphate group forms a stable hydrogen bond network with positively charged residues across the membrane, and the hydrophobic fat chain is fully embedded in the hydrophobic cavity inside the pocket. More importantly, the study found that LPAR5 adopts an atypical Gq coupling mode completely different from classical Class A GPCRs, with the “wavy hook” motif in its activated state specifically targeting the ICL1-Helix8 interface. Functional experiments verified that this unique interface is the core structural basis for LPAR5’s Gq signal selectivity.

This achievement provides precise atomic templates for the rational design of selective small molecule modulators for LPAR5 subtypes, clearing key mechanism barriers for subsequent first-in-class drug development for related indications. The project has received funding from multiple national funds, including the National Natural Science Foundation and the Ministry of Science and Technology’s Key R&D Program.

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9. Gao Yuan’s team at Nanjing Medical University reveals the “immune switch”

of stem cell retinal transplantation On June 17, Gao Yuan’s team at Nanjing Medical University published a groundbreaking original achievement in the top international stem cell journal Cell Stem Cell, clarifying for the first time the key immune regulatory switch of stem cell-derived retinal transplantation, clearing the long-standing barriers to transformation for regenerative therapy of neovascular age-related macular degeneration (nAMD).

As the leading cause of irreversible blindness among the elderly worldwide, existing anti-VEGF targeted therapies for nAMD can only slow the course of the disease and cannot repair completely damaged photoreceptor cells and the retinal pigment epithelium (RPE). Human embryonic stem cell-derived RPE (hESC-RPE) transplantation is recognized as a potentially curative option, but postoperative immune rejection results in a long-term survival rate of less than 30%. Traditional chronic systemic immunosuppression can trigger serious adverse reactions such as infections and metabolic disorders, and has never achieved widespread clinical application.

This study is the first to confirm that the characteristic inflammatory immune microenvironment in vivo, characterized by Th1 bias and IFN-γ enrichment, can reprogram the immunogenicity of hESC-RPE via the JAK1 signaling axis, triggering abnormally high expression of HLA molecules on the cell surface and thereby activating host rejection. The team validated that short-term ex vivo pretreatment with the JAK1 inhibitor rusotinib can significantly reduce HLA-induced expression and reduce immune cell infiltration while fully preserving RPE differentiation function and phototransduction-related paracrine activity. This results in a 217% increase in graft survival rate and 6 months longer duration of visual function recovery compared to the control group in a humanized immunotherapy model, without the need for long-term systemic immunosuppression after surgery.

Currently, the process has completed pilot stability verification and is about to advance to the Pre-IND stage, providing a new low-risk technical pathway for the commercialization of universal ophthalmic stem cell therapies.

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10. Single-cell reveals the mechanism of GALNT7-dependent inhibition of ferroptosis as resistance to immunotherapy

in non-small cell lung cancer Recently, the team from West China Hospital of Sichuan University published their latest translational research findings in the top journal Advanced Science. Relying on a single-cell multi-omics combined functional validation system, they for the first time revealed that abnormal GALNT7-dependent hemostasis pathways in non-small cell lung cancer (NSCLC) are the core mechanism of immune checkpoint blockade (ICB) treatment for primary drug resistance, providing a new direction for breaking through the bottleneck in the benefit rate of immunotherapy for NSCLC.

Currently, the response rate to PD-1/PD-L1 monotherapy in NSCLC clinical trials is only about 20%. Even with combination chemotherapy, more than half of patients still cannot benefit from immunotherapy, with unclear mechanisms of resistance being a core limiting factor. By matching and analyzing multi-omics data from tumor samples from ICB-responding and non-responsive patients, the research team identified that non-responsive patients exhibit an overall “cold tumor” immunosuppressive microenvironment characterized by depleted CD8+ T cell enrichment and myeloid immunosuppressive cell infiltration, while the responding group exhibited a favorable anti-tumor immune landscape with effector T cell activation.

Further research revealed that high GALNT7 expression and global inhibition of the hemostasis pathway together define ICB-resistant tumor cell subpopulations, representing a novel molecular tag for drug resistance. In vivo and in vitro functional experiments confirmed that knockout of GALNT7 can directly inhibit tumor cell proliferation, induce apoptosis, and relieve ferroptosis block, while also reshaping the tumor microenvironment and significantly enhancing the anti-tumor activity of CD8+ T cells. GALNT7 knockout combined with PD-1 blockade can achieve over 80% synergistic tumor suppression effects. This study is the first to clarify that GALNT7 is a core hub molecule connecting ferroptosis regulation and anti-tumor immunity, providing a solid translational basis for developing resistance prediction biomarkers and designing novel sensitization combination regimens for NSCLC ICB treatment.

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