TERT activation targets DNA methylation and multiple aging hallmarks.

Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences p16INK4a expression via upregulation of DNMT3B-mediated promoter hypermethylation. In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis, and preserves cognitive function without evident toxicity, including cancer risk. Together, these findings underscore TERT's critical role in aging processes and provide preclinical proof of concept for physiological TERT activation as a strategy to mitigate multiple aging hallmarks and associated pathologies.

Telomere dysfunction alters intestinal stem cell dynamics to promote cancer.

Telomere dynamics are linked to aging hallmarks, and age-associated telomere loss fuels the development of epithelial cancers. In Apc-mutant mice, the onset of DNA damage associated with telomere dysfunction has been shown to accelerate adenoma initiation via unknown mechanisms. Here, we observed that Apc-mutant mice engineered to experience telomere dysfunction show accelerated adenoma formation resulting from augmented cell competition and clonal expansion. Mechanistically, telomere dysfunction induces the repression of EZH2, resulting in the derepression of Wnt antagonists, which causes the differentiation of adjacent stem cells and a relative growth advantage to Apc-deficient telomere dysfunctional cells. Correspondingly, in this mouse model, GSK3ß inhibition countered the actions of Wnt antagonists on intestinal stem cells, resulting in impaired adenoma formation of telomere dysfunctional Apc-mutant cells. Thus, telomere dysfunction contributes to cancer initiation through altered stem cell dynamics, identifying an interception strategy for human APC-mutant cancers with shortened telomeres.

A Non-π-Conjugated Molecular Crystal with Balanced Second-Harmonic Generation, Bandgap, and Birefringence.

Traditional nonlinear optical (NLO) crystals are exclusively limited to ionic crystals with π-conjugated groups and it is a great challenge to achieve a subtle balance between second-harmonic generation, bandgap, and birefringence for them, especially in the deep-UV spectrum region (Eg  > 6.20 eV). Herein, a non-π-conjugated molecular crystal, NH3 BH3 , which realizes such balance with a large second-harmonic generation response (2.0 × KH2 PO4 at 1064 nm, and 0.45 × ß-BaB2 O4 at 532 nm), deep-UV transparency (Eg > 6.53 eV), and moderate birefringence (Δn = 0.056@550 nm) is reported. As a result, NH3 BH3 exhibits a large quality factor of 0.32, which is evidently larger than those of non-π-conjugated sulfate and phosphate ionic crystals. Using an unpolished NH3 BH3 crystal, effective second-harmonic generation outputs are observed at different wavelengths. These attributes indicate that NH3 BH3 is a promising candidate for deep-UV NLO applications. This work opens up a new door for developing high-performance deep-UV NLO crystals.

Lanthanide-Doped KMgF3 Upconversion Nanoparticles for Photon Avalanche Luminescence with Giant Nonlinearities.

Lanthanide (Ln3+)-doped photon avalanche (PA) upconversion nanoparticles (UCNPs) have great prospects in many advanced technologies; however, realizing efficient PA luminescence in Ln3+-doped UCNPs remains challenging due to the deleterious surface and lattice quenching effect. Herein, we report a unique strategy based on the pyrolysis of KHF2 for the controlled synthesis of aliovalent Ln3+-doped KMgF3 UCNPs, which can effectively protect Ln3+ from luminescence quenching by surface and internal OH- defects and thereby boost upconversion luminescence. This enables us to realize efficient PA luminescence from Tm3+ at 802 nm in KMgF3: Tm3+ UCNPs upon 1064 nm excitation, with a giant nonlinearity of ∼27, a PA response time of 281 ms, and an excitation threshold of 16.6 kW cm-2. This work may open up a new avenue for exploring highly nonlinear PA luminescence through aliovalent Ln3+ doping and crystal lattice engineering toward diverse emerging applications.

Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression.

Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer, KRAS* suppresses antitumor immunity to promote tumor invasion and metastasis. Here, we uncovered that KRAS* transforms the phenotype of carcinoma-associated fibroblasts (CAF) into lipid-laden CAFs, promoting angiogenesis and tumor progression. Mechanistically, KRAS* activates the transcription factor CP2 (TFCP2) that upregulates the expression of the proadipogenic factors BMP4 and WNT5B, triggering the transformation of CAFs into lipid-rich CAFs. These lipid-rich CAFs, in turn, produce VEGFA to spur angiogenesis. In KRAS*-driven colorectal cancer mouse models, genetic or pharmacologic neutralization of TFCP2 reduced lipid-rich CAFs, lessened tumor angiogenesis, and improved overall survival. Correspondingly, in human colorectal cancer, lipid-rich CAF and TFCP2 signatures correlate with worse prognosis. This work unveils a new role for KRAS* in transforming CAFs, driving tumor angiogenesis and disease progression, providing an actionable therapeutic intervention for KRAS*-driven colorectal cancer. SIGNIFICANCE: This study identified a molecular mechanism contributing to KRAS*-driven colorectal cancer progression via fibroblast transformation in the tumor microenvironment to produce VEGFA driving tumor angiogenesis. In preclinical models, targeting the KRAS*-TFCP2-VEGFA axis impaired tumor progression, revealing a potential novel therapeutic option for patients with KRAS*-driven colorectal cancer. This article is featured in Selected Articles from This Issue, p. 2489.

Histone demethylase KDM5D upregulation drives sex differences in colon cancer.

Sex exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular and genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones1. Such sex differences are particularly prominent in colorectal cancer (CRC) in which men experience higher metastases and mortality. A murine CRC model, engineered with an inducible transgene encoding oncogenic mutant KRASG12D and conditional null alleles of Apc and Trp53 tumour suppressors (designated iKAP)2, revealed higher metastases and worse outcomes specifically in males with oncogenic mutant KRAS (KRAS*) CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase KDM5D as a transcriptionally upregulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor. KDM5D-dependent chromatin mark and transcriptome changes showed repression of regulators of the epithelial cell tight junction and major histocompatibility complex class I complex components. Deletion of Kdm5d in iKAP cancer cells increased tight junction integrity, decreased cell invasiveness and enhanced cancer cell killing by CD8+ T cells. Conversely, iAP mice engineered with a Kdm5d transgene to provide constitutive Kdm5d expression specifically in iAP cancer cells showed an increased propensity for more invasive tumours in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes substantially to the sex differences in KRAS* CRC by means of its disruption of cancer cell adhesion properties and tumour immunity, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC.

AIEgen-sensitized lanthanide nanocrystals as luminescent probes for intracellular Fe3+ monitoring.

The abnormal Fe3+ level is known to cause various diseases, such as heart failure, liver damage and neurodegeneration. In situ probing Fe3+ in living cells or organisms is highly desired for both biological research and medical diagnostics. Herein, hybrid nanocomposites NaEuF4@TCPP were constructed by the assembly of an aggregation-induced emission luminogen (AIEgen) TCPP and NaEuF4 nanocrystals (NCs). The anchored TCPP on the surface of NaEuF4 NCs can reduce rotational relaxation of the excited state and efficiently transfer the energy to the Eu3+ ions with minimized nonradiative energy loss. Consequently, the prepared NaEuF4@TCPP nanoparticles (NPs) exhibited an intense red emission with a 103-fold enhancement relative to that in NaEuF4 NCs under 365 nm excitation. A selectively quenching response to Fe3+ ions for the NaEuF4@TCPP NPs makes them luminescent probes for sensitive detection of Fe3+ ions with a low detection limit of 340 nM. Moreover, the luminescence of NaEuF4@TCPP NPs could be recovered by the addition of iron chelators. Benefiting from their good biocompatibility and stability in living cells, together with the characteristic of the reversible luminescence response, the lipo-coated NaEuF4@TCPP probes were successfully applied for real-time monitoring of Fe3+ ions in living HeLa cells. These results are expected to motivate the exploration of AIE-based lanthanide probes for sensing and biomedical applications.

Toward Efficient Two-Photon Circularly Polarized Light Detection through Cooperative Strategies in Chiral Quasi-2D Perovskites.

Organic-inorganic hybrid perovskites carry unique semiconducting properties and advanced flexible crystal structures. These characteristics of organic-inorganic hybrid perovskites create a promising candidacy for circularly polarized light (CPL) detection. However, CPL detections based on chiral perovskites are limited to UV and visible wavelengths. The natural quantum well structures of layered hybrid perovskites generate strong light-matter interactions. This makes it possible to achieve near-infrared (NIR) CPL detection via two-photon absorption in the sub-wavelength region. In this study, cooperative strategies of dimension increase and mixed spacer cations are used to obtain a pair of chiral multilayered perovskites (R-ß-MPA)EA2 Pb2 Br7 and (S-ß-MPA)EA2 Pb2 Br7 (MPA = methylphenethylammonium and EA = ethylammonium). The distinctive bi-cations interlayer and multilayered inorganic skeletons provide enhanced photoconduction. Moreover, superior photoconduction leads to the prominent NIR CPL response with a responsivity up to 8.1 × 10-5 A W-1 . It is anticipated that this work can serve as a benchmark for the fabrication and optimization of efficient NIR CPL detection by simple chemical design.

Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1/CXCR2 results in antitumor immunity and durable response in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is considered non-immunogenic, with trials showing its recalcitrance to PD1 and CTLA4 immune checkpoint therapies (ICTs). Here, we sought to systematically characterize the mechanisms underlying de novo ICT resistance and to identify effective therapeutic options for PDAC. We report that agonist 41BB and antagonist LAG3 ICT alone and in combination, increased survival and antitumor immunity, characterized by modulating T cell subsets with antitumor activity, increased T cell clonality and diversification, decreased immunosuppressive myeloid cells and increased antigen presentation/decreased immunosuppressive capability of myeloid cells. Translational analyses confirmed the expression of 41BB and LAG3 in human PDAC. Since single and dual ICTs were not curative, T cell-activating ICTs were combined with a CXCR1/2 inhibitor targeting immunosuppressive myeloid cells. Triple therapy resulted in durable complete responses. Given similar profiles in human PDAC and the availability of these agents for clinical testing, our findings provide a testable hypothesis for this lethal disease.

Unprecedented Self-Powered Visible-Infrared Dual-Modal Photodetection Induced by a Bulk Photovoltaic Effect in a Polar Perovskite.

Visible-infrared dual-modal light harvesting is crucial for various optoelectronic devices, particularly for solar cells and photodetectors. Hybrid metal-halide perovskites are recently emerging for visible-infrared dual-modal photodetection owing to their prominent multiphoton absorption and carrier transport performances. However, they work relying on an applied external power source or complicated heterostructures. It is still a difficult task to realize visible-infrared dual-modal self-powered photoresponse induced by a bulk photovoltaic effect (BPVE) in a single material. In this work, we constructed a polar multilayered perovskite, (Br-BA)2(EA)2Pb3Br10 (BEP; EA+ = ethylammonium, and Br-BA+ = 4-brombutylammonium). Notably, the polar feature endows BEP with a BPVE. In addition, BEP presents a distinctive two-photon activity arising from the layered quantum-well structure. Benefitting from these striking characteristics, self-powered visible-infrared dual-modal photodetection is realized, and a direct self-powered detection of 800 nm light with a photocurrent of 2.1 nA cm-2 is achieved. This work will inspire the design of desired photoelectric materials with a BPVE for high-performance self-powered visible-infrared dual-modal photodetection.

Boosting the Self-Trapped Exciton Emission in Alloyed Cs2 (Ag/Na)InCl6 Double Perovskite via Cu+ Doping.

Fundamental understanding of the effect of doping on the optical properties of 3D double perovskites (DPs) especially the dynamics of self-trapped excitons (STEs) is of vital importance for their optoelectronic applications. Herein, a unique strategy via Cu+ doping to achieve efficient STE emission in the alloyed lead-free Cs2 (Ag/Na)InCl6 DPs is reported. A small amount (1.0 mol%) of Cu+ doping results in boosted STE emission in the crystals, with photoluminescence (PL) quantum yield increasing from 19.0% to 62.6% and excitation band shifting from 310 to 365 nm. Temperature-dependent PL and femtosecond transient absorption spectroscopies reveal that the remarkable PL enhancement originates from the increased radiative recombination rate and density of STEs, as a result of symmetry breakdown of the STE wavefunction at the octahedral Ag+ site. These findings provide deep insights into the STE dynamics in Cu+ -doped Cs2 (Ag/Na)InCl6 , thereby laying a foundation for the future design of new lead-free DPs with efficient STE emission.

Enhancing Dye-Triplet-Sensitized Upconversion Emission Through the Heavy-Atom Effect in CsLu2 F7 :Yb/Er Nanoprobes.

Lanthanide (Ln3+ )-doped upconversion (UC) nanoprobes, which have drawn extensive attention for various bioapplications, usually suffer from small absorption cross-sections and weak luminescence intensity of Ln3+ ions. Herein, we report the controlled synthesis of a new class of Ln3+ -doped UC nanoprobes based on CsLu2 F7 :Yb/Er nanocrystals (NCs), which can effectively increase the intersystem crossing (ISC) efficiency from singlet excited state to triplet excited state of IR808 up to 99.3 % through the heavy atom effect. By virtue of the efficient triplet sensitization of IR808, the optimal UC luminescence (UCL) intensity of IR808-modified CsLu2 F7 :Yb/Er NCs is enhanced by 1309 times upon excitation at 808 nm. Benefiting from the intense dye-triplet-sensitized UCL, the nanoprobes are demonstrated for sensitive assay of extracellular and intracellular hypochlorite with an 808-nm/980-nm dual excited ratiometric strategy.

AR-negative prostate cancer is vulnerable to loss of JMJD1C demethylase.

Prostate cancer is a leading cause of cancer-related mortality in men. The widespread use of androgen receptor (AR) inhibitors has generated an increased incidence of AR-negative prostate cancer, triggering the need for effective therapies for such patients. Here, analysis of public genome-wide CRISPR screens in human prostate cancer cell lines identified histone demethylase JMJD1C (KDM3C) as an AR-negative context-specific vulnerability. Secondary validation studies in multiple cell lines and organoids, including isogenic models, confirmed that small hairpin RNA (shRNA)-mediated depletion of JMJD1C potently inhibited growth specifically in AR-negative prostate cancer cells. To explore the cooperative interactions of AR and JMJD1C, we performed comparative transcriptomics of 1) isogenic AR-positive versus AR-negative prostate cancer cells, 2) AR-positive versus AR-negative prostate cancer tumors, and 3) isogenic JMJD1C-expressing versus JMJD1C-depleted AR-negative prostate cancer cells. Loss of AR or JMJD1C generates a modest tumor necrosis factor alpha (TNFα) signature, whereas combined loss of AR and JMJD1C strongly up-regulates the TNFα signature in human prostate cancer, suggesting TNFα signaling as a point of convergence for the combined actions of AR and JMJD1C. Correspondingly, AR-negative prostate cancer cells showed exquisite sensitivity to TNFα treatment and, conversely, TNFα pathway inhibition via inhibition of its downstream effector MAP4K4 partially reversed the growth defect of JMJD1C-depleted AR-negative prostate cancer cells. Given the deleterious systemic side effects of TNFα therapy in humans and the viability of JMJD1C-knockout mice, the identification of JMJD1C inhibition as a specific vulnerability in AR-negative prostate cancer may provide an alternative drug target for prostate cancer patients progressing on AR inhibitor therapy.

Unusual Temperature Dependence of Bandgap in 2D Inorganic Lead-Halide Perovskite Nanoplatelets.

Understanding the origin of temperature-dependent bandgap in inorganic lead-halide perovskites is essential and important for their applications in photovoltaics and optoelectronics. Herein, it is found that the temperature dependence of bandgap in CsPbBr3 perovskites is variable with material dimensionality. In contrast to the monotonous redshift ordinarily observed in bulk-like CsPbBr3 nanocrystals (NCs), the bandgap of 2D CsPbBr3 nanoplatelets (NPLs) exhibits an initial blueshift then redshift trend with decreasing temperature (290-10 K). The Bose-Einstein two-oscillator modeling manifests that the blueshift-redshift crossover of bandgap in the NPLs is attributed to the significantly larger weight of contribution from electron-optical phonon interaction to the bandgap renormalization in the NPLs than in the NCs. These new findings may gain deep insights into the origin of bandgap shift with temperature for both fundamentals and applications of perovskite semiconductor materials.

Realization of vis-NIR Dual-Modal Circularly Polarized Light Detection in Chiral Perovskite Bulk Crystals.

Circularly polarized light (CPL)-sensitive direct detection is attracting increasing attention owing to its various optical technology applications and ultracompact device structures. However, current CPL-sensitive direct detection mainly focuses on a single mode, whereas the visible-near-infrared (vis-NIR) dual-modal detection, which is important for improving device sensitivity and night-vision performance, still remains to be explored. Here, for the first time, the vis-NIR dual-modal CPL-sensitive direct detection is presented in bulk single crystals of two-dimensional chiral perovskite (R-BPEA)2PbI4 (R-BPEA = (R)-1-(4-bromophenyl)ethylammonium). Benefiting from the strong light-matter interaction of the layered structure, (R-BPEA)2PbI4 shows a two-photon absorption (TPA) coefficient of up to 55 cm/MW, which almost falls around the highest value of 2D hybrid perovskites. Notably, (R-BPEA)2PbI4 exhibits a high vis-NIR dual-modal CPL-sensitive direct detecting performance under both visible light (520 nm) and NIR light (800 nm), with the on/off ratios of current higher than 103, and the anisotropy factors for photocurrent higher than 0.1. This work will shed light on the design of new chiral semiconductors with a large TPA coefficient and promote their applications in vis-NIR dual-modal CPL-sensitive direct detection.

Anti-dsDNA, anti-nucleosome, anti-C1q, and anti-histone antibodies as markers of active lupus nephritis and systemic lupus erythematosus disease activity.

INTRODUCTION: Previous studies of anti-dsDNA, nucleosome (Nucl), histone (His), and C1q antibodies have revealed their clinical value in systemic lupus erythematosus (SLE). However, the correlation between four autoantibodies and SLE activity, lupus nephritis (LN) remains controversial, and data are insufficient on longitudinal monitoring. This study aimed at evaluating the value of these autoantibodies in active LN, and their performance on cross-sectional evaluating and longitudinal monitoring of SLE disease activity. METHODS: Serum levels of four autoantibodies in 114 SLE patients, 219 other autoimmune disease patients (OAD), and 59 healthy controls were assayed by a quantitative immunoassay. Sera of 38 inpatients were obtained again after treatment. RESULTS: We found that serum levels of four autoantibodies were significantly higher in SLE than OAD patients (p < 001), active LN than non-renal SLE patients (p < .05), and higher in SLE patients with moderate and severe disease activity than mild disease activity (p < .01). Horizontally, serum level of each autoantibody was correlated with SLE disease activity index (SLEDAI) (p < .05), and correlation coefficient of anti-dsDNA was the highest (r = .585). For longitudinal monitoring, the decreased levels of four autoantibodies were found following treatment (p < .001). Serum level variations of these antibodies were positively correlated with variations of SLEDAI (p < .05). The correlation coefficient of anti-Nucl was the highest (r = .629). Although the levels of C3 and C4 increased after treatment, the change was not related to the change of SLEDAI (p > .05). CONCLUSIONS: Anti-C1q, anti-dsDNA, anti-Nucl, and anti-His perform well in diagnosing active LN and monitoring SLE disease activity. They could be indicators of active LN and SLE disease activity.

A Dual-Excitation Decoding Strategy Based on NIR Hybrid Nanocomposites for High-Accuracy Thermal Sensing.

Optical thermal sensing holds great promise for disease theranostics. However, traditional ratiometric thermometry methods, in which intensity ratio of two nonoverlapping emissions is defined as the thermosensitive parameter, may have a limited accuracy in temperature read-out due to the deleterious interference from wavelength- and temperature-dependent photon attenuation in tissue. To overcome this limitation, a dual-excitation decoding strategy based on NIR hybrid nanocomposites comprising self-assembled quantum dots (QDs) and Nd3+ doped fluoride nanocrystals (NCs) is proposed for thermal sensing. Upon excitation at 808 nm, the intensity ratio of two emissions at identical wavelength (1057 nm) from QDs and NCs, respectively, is defined as the thermometric parameter R. By employing another 830 nm laser beam following the same optical path as 808 nm laser to exclusively excite QDs, the two overlapping emissions can be easily decoded. The acquired R proves to be inert to the detection depth in tissue, with a minimized temperature reading error of ≈2.3 °C at 35 °C (at a depth of ≈1.1 mm), while the traditional thermometry mode based on the nonoverlapping 1025 and 863 nm emissions may exhibit a large error of ≈43.0 °C. The insights provided by this work pave the way toward high-accuracy deep-tissue biosensing.

Chromatin Regulator CHD1 Remodels the Immunosuppressive Tumor Microenvironment in PTEN-Deficient Prostate Cancer.

Genetic inactivation of PTEN is common in prostate cancer and correlates with poorer prognosis. We previously identified CHD1 as an essential gene in PTEN-deficient cancer cells. Here, we sought definitive in vivo genetic evidence for, and mechanistic understanding of, the essential role of CHD1 in PTEN-deficient prostate cancer. In Pten and Pten/Smad4 genetically engineered mouse models, prostate-specific deletion of Chd1 resulted in markedly delayed tumor progression and prolonged survival. Chd1 deletion was associated with profound tumor microenvironment (TME) remodeling characterized by reduced myeloid-derived suppressor cells (MDSC) and increased CD8+ T cells. Further analysis identified IL6 as a key transcriptional target of CHD1, which plays a major role in recruitment of immunosuppressive MDSCs. Given the prominent role of MDSCs in suppressing responsiveness to immune checkpoint inhibitors (ICI), our genetic and tumor biological findings support combined testing of anti-IL6 and ICI therapies, specifically in PTEN-deficient prostate cancer. SIGNIFICANCE: We demonstrate a critical role of CHD1 in MDSC recruitment and discover CHD1/IL6 as a major regulator of the immunosuppressive TME of PTEN-deficient prostate cancer. Pharmacologic inhibition of IL6 in combination with immune checkpoint blockade elicits robust antitumor responses in prostate cancer.This article is highlighted in the In This Issue feature, p. 1241.

Effective combinatorial immunotherapy for penile squamous cell carcinoma.

Penile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. Molecular mechanisms and therapies of PSCC are understudied, owing to scarcity of laboratory models. Herein, we describe a genetically engineered mouse model of PSCC, by co-deletion of Smad4 and Apc in the androgen-responsive epithelium of the penis. Mouse PSCC fosters an immunosuppressive microenvironment with myeloid-derived suppressor cells (MDSCs) as a dominant population. Preclinical trials in the model demonstrate synergistic efficacy of immune checkpoint blockade with the MDSC-diminishing drugs cabozantinib or celecoxib. A critical clinical problem of PSCC is chemoresistance to cisplatin, which is induced by Pten deficiency on the backdrop of Smad4/Apc co-deletion. Drug screen studies informed by targeted proteomics identify a few potential therapeutic strategies for PSCC. Our studies have established what we believe to be essential resources for studying PSCC biology and developing therapeutic strategies.

Revisiting the Luminescence Decay Kinetics of Energy Transfer Upconversion.

Energy transfer upconversion (ETU) can efficiently upconvert near-infrared photons into higher-energy photons. Although a comprehensive understanding of ETU is fundamental to the design of ETU materials, the basic excited-state decay kinetics of ETU remains a complicated problem. Here we unravel the mechanism underlying ETU decay in benchmark ß-NaYF4:Er3+ and ß-NaYF4:Ln3+/Yb3+ (Ln = Er, Ho, Tm) ETU microcrystals by combining rate equation analyses with ETU decay measurements. The results show that all of the excited states of one ETU system decay concordantly, with the ETU decay of the emitting state determined by only its intrinsic decay and the product of the ETU decays of the two intermediate states directly responsible for the emitting-state photon upconversion. This general mechanism may serve as a basic rule for excited-state kinetics in upconversion microparticles and nanoparticles, which could provide detailed insight into ETU processes and guide the design of efficient ETU materials.