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Immunotherapies that target programmed cell death protein 1 (PD-1) and its ligand PD-L1 as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) have shown impressive clinical outcomes for multiple tumours. However, only a subset of patients achieves durable responses, suggesting that the mechanisms of the immune checkpoint pathways are not completely understood. Here, we report that PD-L1 translocates from the plasma membrane into the nucleus through interactions with components of the endocytosis and nucleocytoplasmic transport pathways, regulated by p300-mediated acetylation and HDAC2-dependent deacetylation of PD-L1. Moreover, PD-L1 deficiency leads to compromised expression of multiple immune-response-related genes. Genetically or pharmacologically modulating PD-L1 acetylation blocks its nuclear translocation, reprograms the expression of immune-response-related genes and, as a consequence, enhances the anti-tumour response to PD-1 blockade. Thus, our results reveal an acetylation-dependent regulation of PD-L1 nuclear localization that governs immune-response gene expression, and thereby advocate targeting PD-L1 translocation to enhance the efficacy of PD-1/PD-L1 blockade.Gao et al. uncover p300-induced acetylation and HDAC2-mediated deacetylation of PD-L1, which modulate its nuclear translocation to affect the expression of immune genes and the efficacy of anti-PD-1 therapy.

Hund’s multiplicity rule states that a higher spin state has a lower energy for a given electronic configuration 1 . Rephrasing this rule for molecular excited states predicts a positive energy gap between spin-singlet and spin-triplet excited states, as has been consistent with numerous experimental observations over almost a century. Here we report a fluorescent molecule that disobeys Hund’s rule and has a negative singlet–triplet energy gap of −11 ± 2 meV. The energy inversion of the singlet and triplet excited states results in delayed fluorescence with short time constants of 0.2 μs, which anomalously decrease with decreasing temperature owing to the emissive singlet character of the lowest-energy excited state. Organic light-emitting diodes (OLEDs) using this molecule exhibited a fast transient electroluminescence decay with a peak external quantum efficiency of 17%, demonstrating its potential implications for optoelectronic devices, including displays, lighting and lasers. A fluorescent molecule is described that does not follow Hund’s rule and instead shows singlet and triplet excited states with inverted energy levels, leading to high-efficiency OLEDs with potential implications for optoelectronic devices.

Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid progression, early metastasis, and high recurrence rates. Historically considered a homogeneous disease, recent multi-omic studies have revealed distinct molecular subtypes driven by lineage-defining transcription factors, including ASCL1, NEUROD1, POU2F3, and YAP1, as well as an inflamed subtype (SCLC-I). These subtypes exhibit unique therapeutic vulnerabilities, thereby paving the way for precision medicine and targeted therapies. Despite recent advances in molecular classification, tumor heterogeneity, plasticity, and therapy resistance continue to hinder clinical success in treating SCLC patients. To this end, novel therapeutic strategies are being explored, including BCL2 inhibitors, DLL3-targeting agents, Aurora kinase inhibitors, PARP inhibitors, and epigenetic modulators. Additionally, immune checkpoint inhibitors (ICIs) show promise, particularly in immune-enriched subtypes of SCLC patients. Hence, a deeper understanding of SCLC subtype characteristics, evolution, and the regulatory mechanisms of subtype-specific transcription factors is crucial for rationally optimizing precision therapy. This knowledge not only facilitates the identification of subtype-specific therapeutic targets, but also provides a foundation for overcoming resistance and developing personalized combination treatment strategies. In the future, the integration of multi-omic data, dynamic molecular monitoring, and precision medicine approaches are expected to further advance the clinical translation of SCLC subtype-specific therapies, ultimately improving patient survival and outcomes.

Whether glucose is predominantly metabolized via oxidative phosphorylation or glycolysis differs between quiescent versus proliferating cells, including tumor cells. However, how glucose metabolism is coordinated with cell cycle in mammalian cells remains elusive. Here, we report that mammalian cells predominantly utilize the tricarboxylic acid (TCA) cycle in G1 phase, but prefer glycolysis in S phase. Mechanistically, coupling cell cycle with metabolism is largely achieved by timely destruction of IDH1/2, key TCA cycle enzymes, in a Skp2-dependent manner. As such, depleting SKP2 abolishes cell cycle-dependent fluctuation of IDH1 protein abundance, leading to reduced glycolysis in S phase. Furthermore, elevated Skp2 abundance in prostate cancer cells destabilizes IDH1 to favor glycolysis and subsequent tumorigenesis. Therefore, our study reveals a mechanistic link between two cancer hallmarks, aberrant cell cycle and addiction to glycolysis, and provides the underlying mechanism for the coupling of metabolic fluctuation with periodic cell cycle in mammalian cells.

Although inhibitors targeting CDK4/6 kinases (CDK4/6i) have shown promising clinical prospect in treating ER+/HER2- breast cancers, acquired drug resistance is frequently observed and mechanistic knowledge is needed to harness their full clinical potential. Here, we report that inhibition of CDK4/6 promotes βTrCP1-mediated ubiquitination and proteasomal degradation of RB1, and facilitates SP1-mediated CDK6 transcriptional activation. Intriguingly, suppression of CK1ε not only efficiently prevents RB1 from degradation, but also prevents CDK4/6i-induced CDK6 upregulation by modulating SP1 protein stability, thereby enhancing CDK4/6i efficacy and overcoming resistance to CDK4/6i in vitro. Using xenograft and PDX models, we further demonstrate that combined inhibition of CK1ε and CDK4/6 results in marked suppression of tumor growth in vivo. Altogether, these results uncover the molecular mechanisms by which CDK4/6i treatment alters RB1 and CDK6 protein abundance, thereby driving the acquisition of CDK4/6i resistance. Importantly, we identify CK1ε as an effective target for potentiating the therapeutic efficacy of CDK4/6 inhibitors. Acquisition of CDK4/6i resistance represents a major clinical challenge. Here, the authors report that inhibition of CK1ε can prevent acquisition of CDK4/6i resistance, potentiating the therapeutic efficacy of CDK4/6i in human breast cancer.

Activation of the serine-threonine kinase Akt promotes the survival and proliferation of various cancers. Hypoxia promotes the resistance of tumor cells to specific therapies. We therefore explored a possible link between hypoxia and Akt activity. We found that Akt was prolyl-hydroxylated by the oxygen-dependent hydroxylase EglN1. The von Hippel-Lindau protein (pVHL) bound directly to hydroxylated Akt and inhibited Akt activity. In cells lacking oxygen or functional pVHL, Akt was activated to promote cell survival and tumorigenesis. We also identified cancer-associated Akt mutations that impair Akt hydroxylation and subsequent recognition by pVHL, thus leading to Akt hyperactivation. Our results show that microenvironmental changes, such as hypoxia, can affect tumor behaviors by altering Akt activation, which has a critical role in tumor growth and therapeutic resistance.

The prolyl hydroxylation of hypoxia-inducible factor 1α (HIF-1α) mediated by the EGLN–pVHL pathway represents a classic signalling mechanism that mediates cellular adaptation under hypoxia. Here we identify RIPK1, a known regulator of cell death mediated by tumour necrosis factor receptor 1 (TNFR1), as a target of EGLN1–pVHL. Prolyl hydroxylation of RIPK1 mediated by EGLN1 promotes the binding of RIPK1 with pVHL to suppress its activation under normoxic conditions. Prolonged hypoxia promotes the activation of RIPK1 kinase by modulating its proline hydroxylation, independent of the TNFα–TNFR1 pathway. As such, inhibiting proline hydroxylation of RIPK1 promotes RIPK1 activation to trigger cell death and inflammation. Hepatocyte-specific Vhl deficiency promoted RIPK1-dependent apoptosis to mediate liver pathology. Our findings illustrate a key role of the EGLN–pVHL pathway in suppressing RIPK1 activation under normoxic conditions to promote cell survival and a model by which hypoxia promotes RIPK1 activation through modulating its proline hydroxylation to mediate cell death and inflammation in human diseases, independent of TNFR1. Zhang, Xu, Liu, Wang et al. identify an inhibitory mechanism for RIPK1 kinase through EGLN1/pVHL-mediated proline hydroxylation, which is disrupted upon prolonged hypoxia that activates RIPK1 activity to promote cell death and inflammation.

Cancer drug resistance poses a significant challenge in oncology, often driven by intricate cross-talk among membrane-bound receptors that compromise mono-targeted therapies. We develop a dual membrane receptor degradation strategy leveraging Folate Receptor α (FRα) to address this issue. Folate Receptor α Targeting Chimeras-dual (FolTAC-dual) are engineered degraders designed to selectively and simultaneously degrade distinct receptor pairs: (1) EGFR/HER2 and (2) PD-L1/VISTA. Through modular optimization of modality configurations and geometries, we identify the “string” format as the most effective construct. Mechanistic studies demonstrate an ~85% increase in EGFR-binding affinity compared to the conventional knob-into-hole design, likely contributing to the improved efficiency of dual-target degradation. Proof-of-concept studies reveal that EGFR and HER2 FolTAC-dual effectively counteracts resistance in Trastuzumab/Lapatinib-resistant HER2-positive breast cancer models, while PD-L1 and VISTA FolTAC-dual rejuvenates immune responses in PD-L1 antibody-resistant syngeneic mouse models. These findings establish FolTAC-dual as a promising dual-degradation platform for clinical translation. This study presents FolTAC-dual, a folate receptor-mediated platform for dual degradation of EGFR/HER2 and PD-L1/VISTA, offering a strategy to overcome drug resistance and enhance antitumor immunity for cancer treatment.

Phosphorylation of Akt at its carboxy-terminal tail is an essential layer of Akt activation to regulate its physiological functions. Phosphorylation-mediated activation of Akt The serine/threonine protein kinase Akt is an important cellular signalling molecule that functions in a broad range of processes, such as cell proliferation, survival and metabolism. Its activation is known to be controlled by two key phosphorylation sites — one in the catalytic domain and the other in a hydrophobic motif. Here, Wenyi Wei and colleagues show that Akt activity fluctuates across the cell cycle, and phosphorylation by Cdk2/cyclin A or mTORC2 at two sites near the carboxy terminus of the molecule promotes its full activation under distinct physiological conditions. These novel phosphorylation events also seem important in pathological activities of Akt, which include cancer, diabetes and neurological diseases. Akt, also known as protein kinase B, plays key roles in cell proliferation, survival and metabolism. Akt hyperactivation contributes to many pathophysiological conditions, including human cancers 1 , 2 , 3 , and is closely associated with poor prognosis and chemo- or radiotherapeutic resistance 4 . Phosphorylation of Akt at S473 (ref. 5 ) and T308 (ref. 6 ) activates Akt. However, it remains unclear whether further mechanisms account for full Akt activation, and whether Akt hyperactivation is linked to misregulated cell cycle progression, another cancer hallmark 7 . Here we report that Akt activity fluctuates across the cell cycle, mirroring cyclin A expression. Mechanistically, phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation. Furthermore, deletion of the cyclin A2 allele in the mouse olfactory bulb leads to reduced S477/T479 phosphorylation and elevated cellular apoptosis. Notably, cyclin A2-deletion-induced cellular apoptosis in mouse embryonic stem cells is partly rescued by S477D/T479E-Akt1, supporting a physiological role for cyclin A2 in governing Akt activation. Together, the results of our study show Akt S477/T479 phosphorylation to be an essential layer of the Akt activation mechanism to regulate its physiological functions, thereby providing a new mechanistic link between aberrant cell cycle progression and Akt hyperactivation in cancer.

FBW7 acts by affecting apoptosis Loss of the tumour suppressor FBW7 is frequently observed in various types of human cancers, but its mechanism of action as a tumour suppressor remains unclear. Two groups demonstrate that in several cancer types, including ovarian cancer and T-cell leukaemias, the apoptosis regulator MCL1 is targeted for degradation by FBW7. Inuzuka et al . find that this mechanism can determine the response to drugs targeting BCL2 family apoptosis factors, and Wertz et al . show that it is activated during mitotic arrest and determines the response to anti-tubulin chemotherapeutics. Deletion or mutation of FBW7 in patients with cancer can therefore render tumours resistant to these therapies. This is one of two papers demonstrating that in several cancer types including ovarian cancer and T-cell leukaemias, the apoptosis regulator MCL1 is targeted for degradation by the FBW7 tumour suppressor. This study finds that this mechanism can determine the response to drugs targeting BCL2 family apoptosis factors. Deletion or mutation of FBW7 found in cancer patients therefore can render tumours resistant to these therapies. The effective use of targeted therapy is highly dependent on the identification of responder patient populations. Loss of FBW7 , which encodes a tumour-suppressor protein, is frequently found in various types of human cancer, including breast cancer, colon cancer 1 and T-cell acute lymphoblastic leukaemia (T-ALL) 2 . In line with these genomic data, engineered deletion of Fbw7 in mouse T cells results in T-ALL 3 , 4 , 5 , validating FBW7 as a T-ALL tumour suppressor. Determining the precise molecular mechanisms by which FBW7 exerts antitumour activity is an area of intensive investigation. These mechanisms are thought to relate in part to FBW7-mediated destruction of key proteins relevant to cancer, including Jun 6 , Myc 7 , cyclin E 8 and notch 1 (ref. 9 ), all of which have oncoprotein activity and are overexpressed in various human cancers, including leukaemia. In addition to accelerating cell growth 10 , overexpression of Jun, Myc or notch 1 can also induce programmed cell death 11 . Thus, considerable uncertainty surrounds how FBW7-deficient cells evade cell death in the setting of upregulated Jun, Myc and/or notch 1. Here we show that the E3 ubiquitin ligase SCF FBW7 (a SKP1–cullin-1–F-box complex that contains FBW7 as the F-box protein) governs cellular apoptosis by targeting MCL1, a pro-survival BCL2 family member, for ubiquitylation and destruction in a manner that depends on phosphorylation by glycogen synthase kinase 3. Human T-ALL cell lines showed a close relationship between FBW7 loss and MCL1 overexpression. Correspondingly, T-ALL cell lines with defective FBW7 are particularly sensitive to the multi-kinase inhibitor sorafenib but resistant to the BCL2 antagonist ABT-737. On the genetic level, FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737, establishing MCL1 as a therapeutically relevant bypass survival mechanism that enables FBW7 -deficient cells to evade apoptosis. Therefore, our work provides insight into the molecular mechanism of direct tumour suppression by FBW7 and has implications for the targeted treatment of patients with FBW7 -deficient T-ALL.