UHRF2 commissions the completion of DNA demethylation through allosteric activation by 5hmC and K33-linked ubiquitination of XRCC1.

The transition of oxidized 5-methylcytosine (5mC) intermediates into the base excision repair (BER) pipeline to complete DNA demethylation remains enigmatic. We report here that UHRF2, the only paralog of UHRF1 in mammals that fails to rescue Uhrf1-/- phenotype, is physically and functionally associated with BER complex. We show that UHRF2 is allosterically activated by 5-hydroxymethylcytosine (5hmC) and acts as a ubiquitin E3 ligase to catalyze K33-linked polyubiquitination of XRCC1. This nonproteolytic action stimulates XRCC1's interaction with the ubiquitin binding domain-bearing RAD23B, leading to the incorporation of TDG into BER complex. Integrative epigenomic analysis in mouse embryonic stem cells reveals that Uhrf2-fostered TDG-RAD23B-BER complex is functionally linked to the completion of DNA demethylation at active promoters and that Uhrf2 ablation impedes DNA demethylation on latent enhancers that undergo poised-to-active transition during neuronal commitment. Together, these observations highlight an essentiality of 5hmC-switched UHRF2 E3 ligase activity in commissioning the accomplishment of active DNA demethylation.

Pioneer factors for DNA replication initiation in metazoans.

Precise DNA replication is fundamental for genetic inheritance. In eukaryotes, replication initiates at multiple origins that are first "licensed" and subsequently "fired" to activate DNA synthesis. Despite the success in identifying origins with specific DNA motifs in Saccharomyces cerevisiae, no consensus sequence or sequences with a predictive value of replication origins have been recognized in metazoan genomes. Rather, epigenetic rules and chromatin structures are believed to play important roles in governing the selection and activation of replication origins. We propose that replication initiation is facilitated by a group of sequence-specific "replication pioneer factors," which function to increase chromatin accessibility and foster a chromatin environment that is conducive to the loading of the prereplication complex. Dysregulation of the function of these factors may lead to gene duplication, genomic instability, and ultimately the occurrence of pathological conditions such as cancer.

SNP rs4971059 predisposes to breast carcinogenesis and chemoresistance via TRIM46-mediated HDAC1 degradation.

Identification of the driving force behind malignant transformation holds the promise to combat the relapse and therapeutic resistance of cancer. We report here that the single nucleotide polymorphism (SNP) rs4971059, one of 65 new breast cancer risk loci identified in a recent genome-wide association study (GWAS), functions as an active enhancer of TRIM46 expression. Recreating the G-to-A polymorphic switch caused by the SNP via CRISPR/Cas9-mediated homologous recombination leads to an overt upregulation of TRIM46. We find that TRIM46 is a ubiquitin ligase that targets histone deacetylase HDAC1 for ubiquitination and degradation and that the TRIM46-HDAC1 axis regulates a panel of genes, including ones critically involved in DNA replication and repair. Consequently, TRIM46 promotes breast cancer cell proliferation and chemoresistance in vitro and accelerates tumor growth in vivo. Moreover, TRIM46 is frequently overexpressed in breast carcinomas, and its expression is correlated with lower HDAC1 expression, higher histological grades, and worse prognosis of the patients. Together, our study links SNP rs4971059 to replication and to breast carcinogenesis and chemoresistance and support the pursuit of TRIM46 as a potential target for breast cancer intervention.

Latent space search based multimodal optimization with personalized edge-network biomarker for multi-purpose early disease prediction.

Considering that cancer is resulting from the comutation of several essential genes of individual patients, researchers have begun to focus on identifying personalized edge-network biomarkers (PEBs) using personalized edge-network analysis for clinical practice. However, most of existing methods ignored the optimization of PEBs when multimodal biomarkers exist in multi-purpose early disease prediction (MPEDP). To solve this problem, this study proposes a novel model (MMPDENB-RBM) that combines personalized dynamic edge-network biomarkers (PDENB) theory, multimodal optimization strategy and latent space search scheme to identify biomarkers with different configurations of PDENB modules (i.e. to effectively identify multimodal PDENBs). The application to the three largest cancer omics datasets from The Cancer Genome Atlas database (i.e. breast invasive carcinoma, lung squamous cell carcinoma and lung adenocarcinoma) showed that the MMPDENB-RBM model could more effectively predict critical cancer state compared with other advanced methods. And, our model had better convergence, diversity and multimodal property as well as effective optimization ability compared with the other state-of-art methods. Particularly, multimodal PDENBs identified were more enriched with different functional biomarkers simultaneously, such as tissue-specific synthetic lethality edge-biomarkers including cancer driver genes and disease marker genes. Importantly, as our aim, these multimodal biomarkers can perform diverse biological and biomedical significances for drug target screen, survival risk assessment and novel biomedical sight as the expected multi-purpose of personalized early disease prediction. In summary, the present study provides multimodal property of PDENBs, especially the therapeutic biomarkers with more biological significances, which can help with MPEDP of individual cancer patients.

CDK9 inhibition activates innate immune response through viral mimicry.

Cancer cells frequently exhibit hyperactivation of transcription, which can lead to increased sensitivity to compounds targeting the transcriptional kinases, in particular CDK9. However, mechanistic details of CDK9 inhibition-induced cancer cell-selective anti-proliferative effects remain largely unknown. Here, we discover that CDK9 inhibition activates the innate immune response through viral mimicry in cancer cells. In MYC over-expressing prostate cancer cells, CDK9 inhibition leads to the gross accumulation of mis-spliced RNA. Double-stranded RNA (dsRNA)-activated kinase can recognize these mis-spliced RNAs, and we show that the activity of this kinase is required for the CDK9 inhibitor-induced anti-proliferative effects. Using time-resolved transcriptional profiling (SLAM-seq), targeted proteomics, and ChIP-seq, we show that, similar to viral infection, CDK9 inhibition significantly suppresses transcription of most genes but allows selective transcription and translation of cytokines related to the innate immune response. In particular, CDK9 inhibition activates NFκB-driven cytokine signaling at the transcriptional and secretome levels. The transcriptional signature induced by CDK9 inhibition identifies prostate cancers with a high level of genome instability. We propose that it is possible to induce similar effects in patients using CDK9 inhibition, which, we show, causes DNA damage in vitro. In the future, it is important to establish whether CDK9 inhibitors can potentiate the effects of immunotherapy against late-stage prostate cancer, a currently lethal disease.

Epitaxial growth of a 100-square-centimetre single-crystal hexagonal boron nitride monolayer on copper.

The development of two-dimensional (2D) materials has opened up possibilities for their application in electronics, optoelectronics and photovoltaics, because they can provide devices with smaller size, higher speed and additional functionalities compared with conventional silicon-based devices1. The ability to grow large, high-quality single crystals for 2D components-that is, conductors, semiconductors and insulators-is essential for the industrial application of 2D devices2-4. Atom-layered hexagonal boron nitride (hBN), with its excellent stability, flat surface and large bandgap, has been reported to be the best 2D insulator5-12. However, the size of 2D hBN single crystals is typically limited to less than one millimetre13-18, mainly because of difficulties in the growth of such crystals; these include excessive nucleation, which precludes growth from a single nucleus to large single crystals, and the threefold symmetry of the hBN lattice, which leads to antiparallel domains and twin boundaries on most substrates19. Here we report the epitaxial growth of a 100-square-centimetre single-crystal hBN monolayer on a low-symmetry Cu (110) vicinal surface, obtained by annealing an industrial copper foil. Structural characterizations and theoretical calculations indicate that epitaxial growth was achieved by the coupling of Cu <211> step edges with hBN zigzag edges, which breaks the equivalence of antiparallel hBN domains, enabling unidirectional domain alignment better than 99 per cent. The growth kinetics, unidirectional alignment and seamless stitching of the hBN domains are unambiguously demonstrated using centimetre- to atomic-scale characterization techniques. Our findings are expected to facilitate the wide application of 2D devices and lead to the epitaxial growth of broad non-centrosymmetric 2D materials, such as various transition-metal dichalcogenides20-23, to produce large single crystals.

Chromodomain Protein CDYL Acts as a Crotonyl-CoA Hydratase to Regulate Histone Crotonylation and Spermatogenesis.

Lysine crotonylation (Kcr) is a newly identified histone modification that is associated with active transcription in mammalian cells. Here we report that the chromodomain Y-like transcription corepressor CDYL negatively regulates histone Kcr by acting as a crotonyl-CoA hydratase to convert crotonyl-CoA to ß-hydroxybutyryl-CoA. We showed that the negative regulation of histone Kcr by CDYL is intrinsically linked to its transcription repression activity and functionally implemented in the reactivation of sex chromosome-linked genes in round spermatids and genome-wide histone replacement in elongating spermatids. Significantly, Cdyl transgenic mice manifest dysregulation of histone Kcr and reduction of male fertility with a decreased epididymal sperm count and sperm cell motility. Our study uncovers a biochemical pathway in the regulation of histone Kcr and implicates CDYL-regulated histone Kcr in spermatogenesis, adding to the understanding of the physiology of male reproduction and the mechanism of the spermatogenic failure in AZFc (Azoospermia Factor c)-deleted infertile men.

Reconstruction of High Entropy Alloys on a Metal-Organic Framework Approaching Active Oxygen Reduction Electrocatalysts.

High-entropy alloys (HEAs) have garnered considerable attention as promising nanocatalysts for effectively utilizing Pt in catalysis toward oxygen reduction reactions due to their unique properties. Nonetheless, there is a relative dearth of attention regarding the structural evolution of HEAs in response to electrochemical conditions. In this work, we propose a thermal reduction method to synthesize high entropy nanoparticles by leveraging the confinement effect and abundant nitrogen-anchored sites provided by pyrolyzed metal-organic frameworks (MOFs). Notably, the prepared catalysts exhibit enhanced activity accompanied by structural reconstruction during electrochemical activation, approaching 1 order of magnitude higher mass activity compared to Pt/C in oxygen reduction. Atomic-scale structural characterization reveals that abundant defects and single atoms are formed during the activation process, contributing to a significant boost in the catalytic performance for oxygen reduction reactions. This study provides deep insights into surface reconstruction engineering during electrochemical operations, with practical implications for fuel cell applications.

Optically Probing Unconventional Superconductivity in Atomically Thin Bi2Sr2Ca0.92Y0.08Cu2O8+δ.

Atomically thin cuprates exhibiting a superconducting phase transition temperature similar to that of the bulk have recently been realized, although the device fabrication remains a challenge and limits the potential for many novel studies and applications. Here, we use an optical pump-probe approach to noninvasively study the unconventional superconductivity in atomically thin Bi2Sr2Ca0.92Y0.08Cu2O8+δ (Y-Bi2212). Apart from finding an optical response due to the superconducting phase transition that is similar to that of bulk Y-Bi2212, we observe that the sign and amplitude of the pump-probe signal in atomically thin flakes vary significantly in different dielectric environments depending on the nature of the optical excitation. By exploiting the spatial resolution of the optical probe, we uncover the exceptional sensitivity of monolayer Y-Bi2212 to the environment. Our results provide the first optical evidence for the intralayer nature of the superconducting condensate in Bi2212 and highlight the role of double-sided encapsulation in preserving superconductivity in atomically thin cuprates.

DWARF AND LOW-TILLERING 2 functions in brassinosteroid signaling and controls plant architecture and grain size in rice.

Brassinosteroids (BRs) are a class of steroid phytohormones that control various aspects of plant growth and development. Several transcriptional factors (TFs) have been suggested to play roles in BR signaling. However, their possible relationship remains largely unknown. Here, we identified a rice mutant dwarf and low-tillering 2 (dlt2) with altered plant architecture, increased grain width, and reduced BR sensitivity. DLT2 encodes a GIBBERELLIN INSENSITIVE (GAI)-REPRESSOR OF GAI (RGA)-SCARECROW (GRAS) TF that is mainly localized in the nucleus and has weak transcriptional activity. Our further genetic and biochemical analyses indicate that DLT2 interacts with two BR-signaling-related TFs, DLT and BRASSINAZOLE-RESISTANT 1, and probably modulates their transcriptional activity. These findings imply that DLT2 is implicated in a potentially transcriptional complex that mediates BR signaling and rice development and suggests that DLT2 could be a potential target for improving rice architecture and grain morphology. This work also sheds light on the role of rice GRAS members in regulating numerous developmental processes.

Boosting the Electrical Transfer by Molybdenum Doping for Robust and Flexible NiSe-Based Supercapacitor.

NiSe is a promising electrode material for enhancing the energy density of supercapacitors, but it faces challenges such as sensitivity to electrolyte anions, limited specific capacity, and unstable cycling. This study employs a strategy of metal atom doping to address these issues. Through a hydrothermal reaction, Mo-doped NiSe demonstrates significant improvement in electrochemical performance, exhibiting high capacity (799.90 C g-1), splendid rate performance, and excellent cyclic stability (90% capacity retention). The introduction of Mo induces charge redistribution in NiSe, leading to a reduction in the band gap. Theoretical calculation reveals that Mo doping can effectively enhance the electrical conductivity and the adsorption energy of NiSe. A flexible printed hybrid Mo-doped NiSe-based supercapacitor is fabricated, demonstrating superior electrochemical performance (367.04 mF cm-2) and the ability to power timers, LEDs, and toy fans. This research not only deepens the understanding of the electrochemical properties of metal-doped NiSe but also highlights its application potential in high-performance supercapacitors.

Fully-Printed Flexible Aqueous Rechargeable Sodium-Ion Batteries.

The flexible aqueous rechargeable sodium-ion batteries (ARSIBs) are a promising portable energy storage system that can meet the flexibility and safety requirements of wearable electronic devices. However, it faces huge challenges in mechanical stability and facile manufacturing processes. Herein, the first fully-printed flexible ARSIBs with appealing mechanical performance by screen-printing technique is prepared, which utilizes Na3V2(PO4)2F3/C (NVPF/C) as the cathode and 2% nitrogenous carbon-loaded Na3MnTi(PO4)3/C (NMTP/C/NC) as the anode. In particular, the organic co-solvent ethylene glycol (EG) is cleverly added to 17 m (mol kg-1) NaClO4 electrolyte to prepare a 17 m NaClO4-EG mixed electrolyte. This mixed electrolyte can withstand low temperatures of -20 °C in practical applications. Encouragingly, the fully-printed flexible ARSIBs (NMTP/C/NC//NVPF/C) exhibit a discharge capacity of 40.1 mAh g-1, an energy density of 40.1 Wh kg-1, and outstanding cycle performance. Moreover, these batteries with various shapes can be used as an energy wristband for an electronic watch in the bending states. The fully-printed flexible ARSIBs in this work are expected to shed light on the development of energy for wearable electronics.

Copper as an Electron Hunter for Enhancing Bi2O2CO3 Electrocatalytic CO2 Conversion to Formate.

Cu-doped Bi2O2CO3 catalyst with copper (Cu) acting an electron hunter for conversion of carbon dioxide into formate is developed. The Cu-Bi2O2CO3 catalyst with hollow microsphere structure extends the duration of CO2 retention on the catalyst, providing a greater number of active sites. It exhibits remarkable performance with conversion efficacy of 98.5% and current density of 800 mA cm-2 across a wide potential window (-0.8 to -1.3 V vs RHE). Density functional theory investigations reveal that the presence of copper (Cu) significantly enhances the charge density at the active sites and influences the local electronic structure of bismuth (Bi), thereby reducing the energy barrier associated with the transformation of *OCHO species into formate.

Realization of High-Performance Self-Powered Polarized Photodetection with Large Temperature Window in a 2D Polar Perovskite.

Polarization photodetection taking advantage of the anisotropy of 2D materials shines brilliantly in optoelectronic fields owing to differentiating optical information. However, the previously reported polarization detections are mostly dependent on external power sources, which is not conducive to device integration and energy conservation. Herein, a 2D polar perovskite (CBA)2CsPb2Br7 (CCPB, CBA = 4-chlorobenzyllamine) has been successfully synthesized, which shows anticipated bulk photovoltaic effect (BPVE) with an open-circuited photovoltage up to ≈0.2 V. Devices based on CCPB monomorph fulfill a fascinating self-powered polarized photodetection with a large polarization ratio of 2.7 at room temperature. Moreover, CCPB features a high phase-transition temperature (≈475 K) which prompts such self-powered polarized photodetection in a large temperature window of device operation, since BPVE generated by spontaneous polarization can only exist in the polar structure prior to the phase transition. Further computational investigation reveals the introduction of CBA+ with a large dipole moment contributes to quite large polarization (17.5 µC cm-2) and further super high phase transition temperature of CCPB. This study will promote the application of 2D perovskite materials for self-powered polarized photodetection in high-temperature conditions.

Multi-modal optimization to identify personalized biomarkers for disease prediction of individual patients with cancer.

Finding personalized biomarkers for disease prediction of patients with cancer remains a massive challenge in precision medicine. Most methods focus on one subnetwork or module as a network biomarker; however, this ignores the early warning capabilities of other modules with different configurations of biomarkers (i.e. multi-modal personalized biomarkers). Identifying such modules would not only predict disease but also provide effective therapeutic drug target information for individual patients. To solve this problem, we developed a novel model (denoted multi-modal personalized dynamic network biomarkers (MMPDNB)) based on a multi-modal optimization mechanism and personalized dynamic network biomarker (PDNB) theory, which can provide multiple modules of personalized biomarkers and unveil their multi-modal properties. Using the genomics data of patients with breast or lung cancer from The Cancer Genome Atlas database, we validated the effectiveness of the MMPDNB model. The experimental results showed that compared with other advanced methods, MMPDNB can more effectively predict the critical state with the highest early warning signal score during cancer development. Furthermore, MMPDNB more significantly identified PDNBs containing driver and biomarker genes specific to cancer tissues. More importantly, we validated the biological significance of multi-modal PDNBs, which could provide effective drug targets of individual patients as well as markers for predicting early warning signals of the critical disease state. In conclusion, multi-modal optimization is an effective method to identify PDNBs and offers a new perspective for understanding tumor heterogeneity in cancer precision medicine.

The integration of multidisciplinary approaches revealed PTGES3 as a novel drug target for breast cancer treatment.

BACKGROUND: The main challenge in personalized treatment of breast cancer (BC) is how to integrate massive amounts of computing resources and data. This study aimed to identify a novel molecular target that might be effective for BC prognosis and for targeted therapy by using network-based multidisciplinary approaches. METHODS: Differentially expressed genes (DEGs) were first identified based on ESTIMATE analysis. A risk model in the TCGA-BRCA cohort was constructed using the risk score of six DEGs and validated in external and clinical in-house cohorts. Subsequently, independent prognostic factors in the internal and external cohorts were evaluated. Cell viability CCK-8 and wound healing assays were performed after PTGES3 siRNA was transiently transfected into the BC cell lines. Drug prediction and molecular docking between PTGES3 and drugs were further analyzed. Cell viability and PTGES3 expression in two BC cell lines after drug treatment were also investigated. RESULTS: A novel six-gene signature (including APOOL, BNIP3, F2RL2, HINT3, PTGES3 and RTN3) was used to establish a prognostic risk stratification model. The risk score was an independent prognostic factor that was more accurate than clinicopathological risk factors alone in predicting overall survival (OS) in BC patients. A high risk score favored tumor stage/grade but not OS. PTGES3 had the highest hazard ratio among the six genes in the signature, and its mRNA and protein levels significantly increased in BC cell lines. PTGES3 knockdown significantly inhibited BC cell proliferation and migration. Three drugs (gedunin, genistein and diethylstilbestrol) were confirmed to target PTGES3, and genistein and diethylstilbestrol demonstrated stronger binding affinities than did gedunin. Genistein and diethylstilbestrol significantly inhibited BC cell proliferation and reduced the protein and mRNA levels of PTGES3. CONCLUSIONS: PTGES3 was found to be a novel drug target in a robust six-gene prognostic signature that may serve as a potential therapeutic strategy for BC.

Imaging diagnosis and differential diagnosis of extraskeletal osteosarcoma.

OBJECTIVE: The aim of this study was to investigate the clinical, imaging and pathological features of extraskeletal osteosarcoma (EOS) and to improve the understanding of this disease and other similar lesions. METHODS: The data for 11 patients with pathologically confirmed extraosseous osteosarcoma, including tumour site and size and imaging and clinical manifestations, were analysed retrospectively. RESULTS: Six patients were male (60%), and 5 were female (40%); patient age ranged from 23 to 76 years (average age 47.1 years). Among the 11 patients, 7 had clear calcifications or ossification with different morphologies, and 2 patients showed a massive mature bone tumour. MRI showed a mixed-signal mass with slightly longer T1 and T2 signals in the tumour parenchyma. Enhanced CT and MRI scans showed enhancement in the parenchyma. Ten patients had different degrees of necrosis and cystic degeneration in the mass, 2 of whom were complicated with haemorrhage, and MRI showed "fluid‒fluid level" signs. Of the 11 patients, five patients survived after surgery, and no obvious recurrence or metastasis was found on imaging examination. One patient died of lung metastasis after surgery, and 2 patients with open biopsy died of disease progression. One patient died of respiratory failure 2 months after operation. 2 patients had positive surgical margins, and 1 had lung metastasis 6 months after operation and died 19 months after operation. Another patient had recurrence 2 months after surgery. CONCLUSION: The diagnosis of EOS requires a combination of clinical, imaging and histological examinations. Cystic degeneration and necrosis; mineralization is common, especially thick and lumpy mineralization. Extended resection is still the first choice for localized lesions. For patients with positive surgical margins or metastases, adjuvant chemoradiotherapy is needed.

Loss of NLRP6 expression increases the severity of intestinal injury after syngeneic hematopoietic stem cell transplantation.

NLRP6 plays a crucial role in maintaining intestinal homeostasis by regulating the interaction between the intestinal mucosa and the microbiota. However, the impact of NLRP6 deficiency on intestinal damage following hematopoietic stem cell transplantation (HSCT) remains poorly understood. In this study, we established a syngeneic HSCT mouse model using C57BL/6 mice as donors and NLRP6-/- or C57BL/6 mice as recipients. Our findings revealed that NLRP6 deficiency had minimal influence on peripheral blood cell counts and splenic immune cell proportions in transplanted mice. However, it exacerbated pathological changes in the small intestine on day 14 post-transplantation, accompanied by increased proportions of macrophages, dendritic cells, and neutrophils. Furthermore, the NLRP6 deficiency resulted in elevated expression of MPO and CD11b, while reducing the levels mature caspase-1 and mature IL-1ß in the intestine. Moreover, the NLRP6 deficiency disturbed the expression of apoptosis-related molecules and decreased the tight junction protein occludin. Notably, recipient mice with NLRP6 deficiency exhibited lower mRNA expression levels of antimicrobial genes, such as Reg3γ and Pla2g2a. The short-term increase in inflammatory cell infiltration caused by NLRP6 deficiency was associated with intestinal damage, increased apoptosis, reduced expression of antimicrobial peptides, and impaired intestinal repair. Taken together, our findings demonstrate that the loss of NLRP6 exacerbates post-transplantation intestinal damage in recipient mice.

Alpha and beta/low-gamma frequency bands may have distinct neural origin and function during post-stroke walking.

Plantarflexors provide propulsion during walking and receive input from both corticospinal and corticoreticulospinal tracts, which exhibit some frequency-specificity that allows potential differentiation of each tract's descending drive. Given that stroke may differentially affect each tract and impair the function of plantarflexors during walking; here, we examined this frequency-specificity and its relation to walking-specific measures during post-stroke walking. Fourteen individuals with chronic stroke walked on an instrumented treadmill at self-selected and fast walking speed (SSWS and FWS, respectively) while surface electromyography (sEMG) from soleus (SOL), lateral gastrocnemius (LG), and medial gastrocnemius (MG) and ground reaction forces (GRF) were collected. We calculated the intermuscular coherences (IMC; alpha, beta, and low-gamma bands between SOL-LG, SOL-MG, LG-MG) and propulsive impulse using sEMG and GRF, respectively. We examined the interlimb and intralimb IMC comparisons and their relationships with propulsive impulse and walking speed. Interlimb IMC comparisons revealed that beta LG-MG (SSWS) and low-gamma SOL-LG (FWS) IMCs were degraded on the paretic side. Intralimb IMC comparisons revealed that only alpha IMCs (both speeds) exhibited a statistically significant difference to random coherence. Further, alpha LG-MG IMC was positively correlated with propulsive impulse in the paretic limb (SSWS). Alpha and beta/low-gamma bands may have a differential functional role, which may be related to the frequency-specificity of the underlying descending drives. The persistence of alpha band in plantarflexors and its strong positive relationship with propulsive impulse suggests relative alteration of corticoreticulospinal tract after stroke. These findings imply the presence of frequency-specific descending drives to walking-specific muscles in chronic stroke.

Effect of CDK4/6 Inhibitors on Tumor Immune Microenvironment.

Cancer is an abnormal proliferation of cells that is stimulated by cyclin-dependent kinases (CDKs) and defective cell cycle regulation. The essential agent that drive the cell cycle, CDK4/6, would be activated by proliferative signals. Activated CDK4/6 results in the phosphorylation of the neuroblastoma protein (RB) and the release of the transcription factor E2F, which promotes the cell cycle progression. CDK4/6 inhibitor (CDK4/6i) has been currently a research focus, which inhibits the CDK4/6-RB-E2F axis, thereby reducing the cell cycle transition from G1 to S phase and mediating the cell cycle arrest. This action helps achieve an anti-tumor effect. Recent research has demonstrated that CDK4/6i, in addition to contributing to cell cycle arrest, is also essential for the interaction between the tumor cells and the host immune system, i.e., activating the immune system, strengthening the tumor antigen presentation, and reducing the number of regulatory T cells (Treg). Additionally, CDK4/6i would elevate the level of PD-L1, an immunosuppressive factor, in tumor cells, and CDK4/6i in combination with anti-PD-L1 therapy would more effectively reduce the tumor growth. Our results showed that CDK4/6i caused autophagy and senescence in tumor cells. Herein, the impact of CDK4/6i on the immune microenvironment of malignant tumors was mainly focused, as well as their interaction with immune checkpoint inhibitors in affecting anti-tumor immunity.