Exercise mitigates chemotherapy-related cardiotoxicity, but implementing exercise interventions during chemotherapy treatment can be challenging. Understanding the patient perspective can help refine exercise programs and facilitate successful implementation of future interventions.

Although cancer incidence is increasing globally, early detection and antineoplastic treatment ensure high patient survival rates. Among the chemotherapeutic agents widely used clinically, cisplatin is associated with the development of painful and non-painful peripheral neuropathy symptoms, compromising patient treatment continuity. Preclinical studies have indicated that the transient receptor potential vanilloid 1 (TRPV1) ion channels play a crucial role in chemotherapy-induced neuropathic pain. Currently, only duloxetine is recommended for treating chemotherapy-induced peripheral neuropathy, highlighting the urgent need for novel therapies. Natural products such as diosmetin have shown promising pharmacological potential. Here, we evaluated the effects of diosmetin in a mouse model of cisplatin-induced neuropathic pain (0.23 mg/kg, intraperitoneal). Nociceptive parameters included mechanical allodynia, affective-motivational behaviour, heat hyperalgesia, and muscle strength loss, along with hepatic [aspartate aminotransferase (AST), alanine aminotransferase (ALT)] and renal (urea and creatinine) biomarkers. Diosmetin (0.015, 0.15, and 1.5 mg/kg) administered orally by gavage (p.o.) resulted in antinociceptive effects, reduced mechanical allodynia, and decreased affective motivational behaviours in mice. Diosmetin (0.15 mg/kg) also reduced cisplatin-induced heat hyperalgesia and muscle strength loss, showing an efficacy comparable to that of duloxetine (30 mg/kg, p.o., positive control) and SB-366791 (1 mg/kg p.o., TRPV1 channel antagonist). Additionally, prior desensitisation of TRPV1-positive fibres with subcutaneous resiniferatoxin (RTX) prevents the development of mechanical allodynia and thermal hyperalgesia. Diosmetin (0.15 mg/kg) did not alter hepatic or renal biomarkers. Diosmetin has therapeutic potential for treating pain in patients with neuropathy, and the TRPV1 channel plays a crucial role in cisplatin-induced peripheral neuropathy.

Immune checkpoint blockade (ICB) targeting PD-1/PD-L1 improves outcomes across multiple malignancies, yet resistance to immune checkpoint blockade remains common. Here, we identify HILPDA as a tumor-intrinsic regulator of immune evasion in breast cancer. HILPDA overexpression increases the infiltration and suppressive activity of regulatory T cells while decreasing the infiltration, activation, and cytotoxicity of CD8+ T cells and natural killer cells, thereby establishing an immunosuppressive tumor microenvironment. Mechanistically, HILPDA binds to HSP90 and protects the transcription factor KLF5 from proteasomal degradation, sustaining fatty acid synthesis and lipid droplet accumulation. The resulting increase in palmitate augments PD-L1 palmitoylation at cysteine 272, enhancing PD-L1 membrane localization and palmitoylation-dependent stability and maintaining inhibitory signaling. We further showed that the E3 ligase TRIM21 mediates K63-linked polyubiquitination of HILPDA and promotes its degradation. In breast cancer models, pharmacologic engagement of TRIM21 with fenretinide decreases PD-L1 palmitoylation, reprograms the tumor microenvironment toward cytotoxic immunity, restores antitumor responses, and improves anti-PD-1 efficacy. Collectively, these results indicate that HILPDA-driven lipogenesis increases PD-L1 palmitoylation, leading to immune evasion and ICB resistance, and TRIM21/HILPDA-targeted combinations are proposed as a therapeutic strategy.

Metastatic clear cell renal cell carcinoma (ccRCC) remains lethal due to therapy resistance, and while dysregulated Wnt/β-catenin signaling drives progression, its post-translational regulation is poorly understood. Through multi-omics analysis of TCGA/GEO datasets, we identified MAGI3 as a key metastasis suppressor in ccRCC. Functional validation revealed that MAGI3 loss enhances invasion, migration and metastatic potential in vitro and in vivo. Mechanistically, MAGI3 binds β-catenin's C-terminus via PDZ domains, disrupting intramolecular N-terminus-ARM domain interactions to expose phosphorylation sites, thereby enabling GSK-3β-mediated β-catenin phosphorylation and ubiquitin-dependent degradation. Critically, low MAGI3 hyperactivates β-catenin and drives mTOR inhibitor resistance. Combining Everolimus with the Wnt inhibitor XAV-939 slashed viability and invasion in resistant cells. Clinically, patients whose tumors exhibited high MAGI3 and low β-catenin expression demonstrated significantly improved response to Everolimus therapy. In conclusion, MAGI3 is a critical gatekeeper of β-catenin destruction in ccRCC. Its loss defines a metastatic, therapy-resistant subtype targetable by dual mTOR/Wnt blockade. Therefore, MAGI3 expression may stratify patients for personalized therapy.

Objective: To exploit the elevated glutathione (GSH) levels in the tumor microenvironment and investigate the therapeutic efficacy of a novel glutathione-responsive apurinic/apyrimidinic (AP) site captor, Probe-NEt, against anaplastic thyroid cancer (ATC). Methods: Fluorescence imaging compared Probe-NEt uptake and activation in normal thyroid (Nthy ori 3-1), ATC (THJ-16T, CAL-62), and lung cancer (H1299) cells. Half maximal inhibitory concentration (IC50) values were determined by cytotoxicity assays; DNA damage was evaluated using appropriate assays. Flow cytometry analyzed cell cycle distribution and apoptosis following treatment with low (5 μmol/L) or high (20 μmol/L) Probe-NEt concentrations. BALB/c nude mice bearing subcutaneous ATC xenografts received low (0.025 mg) or high (0.05 mg) dose injections. Tumor volumes were monitored; HE staining assessed biosafety in major organs; immunohistochemistry detected apoptosis-related protein expression. Results: ATC cells demonstrated significantly higher Probe-NEt activation than normal thyroid cells. Probe-NEt exhibited selective cytotoxicity (higher IC50 in normal vs. ATC cells; all P＜0.01) with time-dependent characteristics; the selectivity ratio increased from 1.7 at 24 h (62.4 vs. 37.7 μmol/L) to 2.4 at 48 h (32.7 vs. 13.5 μmol/L). Probe-NEt induced DNA damage, G2/M arrest (THJ-16T: from 5% to 43%; CAL-62: from 19% to 37%), and dose-dependent late apoptosis. In THJ-16T cells, late apoptotic rates rose from 5.49% (control) to 13.95% (low-dose) and 63.43% (high-dose), with viable cells decreasing accordingly (89.42%, 76.01%, 20.45%). CAL-62 cells showed similar trends (16.72%, 40.19%, 69.88%). In vivo, Probe-NEt significantly suppressed tumor growth without hepatorenal toxicity (all P＞0.167). Immunohistochemistry revealed upregulated pro-apoptotic proteins, downregulated anti-apoptotic proteins, and decreased Ki-67 expression. Conclusion: The glutathione-responsive AP site captor Probe-NEt significantly inhibits ATC cell growth, induces G2/M phase cell cycle arrest, promotes late apoptosis, and exhibits high selectivity and favorable biosafety profiles.

In recent years, antibody-drug conjugates (ADCs) have achieved remarkable progress in the treatment of solid tumors and are now widely applied in malignancies such as breast cancer, ovarian cancer, cervical cancer, urothelial carcinoma, and non-small cell lung cancer, demonstrating favorable clinical efficacy. However, with their expanding clinical use, safety challenges associated with ADCs have become increasingly apparent. Among these, ocular adverse events have received limited attention in the past but is now emerging as a clinically relevant concern, as it may impair patients' quality of life and necessitate treatment modifications. Due to differences in payloads, target specificity, and mechanisms of action, various ADCs may induce ocular adverse events, including corneal disorders such as dry eye and keratoconjunctivitis, which can lead to visual disturbances, diminished quality of life, and reduced treatment adherence. Consequently, appropriate preventive and management strategies are urgently needed in clinical practice. To address this gap, and based on the latest international and domestic clinical evidence as well as multidisciplinary expert experience in oncology and ophthalmology, a Chinese expert consensus was developed following extensive discussion. This consensus aims to enhance clinicians' awareness of ADC-associated ocular adverse events, promote the safe application of ADCs in the treatment of solid tumors, and ultimately improve patients' quality of life and therapeutic outcomes.

Proteolysis-targeting chimeras (PROTACs) offer a catalytic strategy for sustained oncogenic protein suppression. Here, we applied a "natural product PROTACylation" approach, utilizing maslinic acid (MA) as the JAK2-targeting warhead and lenalidomide as the CRBN recruiter to generate a focused library of 18 compounds (SZ1-SZ18). Lead compound P4 (SZ15), featuring a 14-atom linker, demonstrated superior antiproliferative activity compared to the parent MA across multiple cancer cell lines, with IC50 values of 6.57 μM (MCF-7), 11.73 μM (HeLa), and 9.56 μM (A549). Structure-activity relationship analysis revealed that linker length critically modulates cytotoxicity and selectivity, with the optimized linker enabling productive ternary complex formation. Mechanistic studies confirmed that P4 induces time-dependent, proteasome-mediated degradation of JAK2, reaching maximal protein reduction at 48 h. Competitive inhibition experiments using excess MA or lenalidomide, along with MLN4924 treatment, validated the requirement for ternary complex formation and cullin-RING E3 ligase pathway dependence. Direct MA-JAK2 engagement was demonstrated through CETSA and DARTS assays, supporting MA's suitability as a POI ligand. Molecular docking revealed preferential binding of P4 to JAK2 over CRBN (-8.7 vs -7.7 kcal/mol), suggesting an initial JAK2 anchoring mechanism that facilitates catalytically competent ternary complex assembly. Functionally, P4 exhibits comprehensive antitumor activity in A549 cells, suppressing clonogenic growth and invasion while inducing robust apoptosis (≥80% at 20 μM) and G0/G1 phase arrest. P4 effectively downregulates the IL-6/JAK2/STAT3 signaling axis and simultaneously activates dual apoptotic pathways: intrinsic mitochondrial apoptosis (decreased Bcl-2, XIAP, survivin; increased Bax, cytochrome c, cleaved caspases) and ER stress-mediated apoptosis (elevated IRE1, BIP, ATF4, CHOP, p-JNK1, cleaved caspase-12). This work establishes P4 as a promising JAK2-targeting degrader whose anticancer efficacy derives from coordinated target elimination, oncogenic pathway suppression, and dual apoptotic pathway activation, validating natural product PROTACylation as a viable strategy for developing multifunctional anticancer therapeutics.

Excessive RNA damage activates cellular stress responses, triggering cell death. However, pathways that negatively regulate RNA damage responses are largely uncharacterized. Using genetic screens, we find that the ubiquitin ligase RNF25 provides tolerance to RNA damage caused by the nucleoside analogue azacytidine, a chemotherapeutic agent used to treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Mechanistically, we show that azacytidine is incorporated into mRNA, where it causes lesions that stall elongating ribosomes, leading to cytotoxic activation of the GCN2-dependent integrated stress response (ISR). Furthermore, we establish that RNF25 prevents ISR hyperactivation by ubiquitylation of ribosomal protein eS31, thereby suppressing cell death upon azacytidine treatment. Our study reveals an mRNA damage tolerance mechanism that determines cellular survival in response to azacytidine, highlighting RNA damage-induced stress response as a potentially critical component of chemosensitivity in AML and MDS.

In this quick guide Zhang et al. introduce the microtubule disassembly inhibitor and potent anti-cancer drug paclitaxel, describing where it is sourced and its mode of action as well as future production strategies.

Tumor progression is critically shaped by the dynamic interplay between tumor cells and the tumor microenvironment (TME). The TME harbors a diverse array of immune cells, encompassing T cell, B cell, NK cell and macrophages. Among these, TAMs profoundly shape tumor growth and metastasis by interacting with tumor cells and other immune cells. To adapt to the varied immune and metabolic cues in the TME, they undergo dynamic metabolic reprogramming, which recent advances have shown to involve extensive remodeling of glucose, lipid, and amino acid metabolism, along with the tricarboxylic acid cycle. However, critical knowledge gaps remain regarding the cellular heterogeneity of TAM metabolic reprogramming, divergent metabolic signatures across TAM subsets, and context-dependent variations in metabolic rewiring among different cancer types. However, the mechanisms by which these metabolic alterations translate into distinct functional phenotypes and shape the immune landscape of the TME remain poorly defined. This review systematically synthesizes the current knowledge on how metabolic remodeling in TAMs regulates their polarization and pro-tumor functions. We specifically focus on delineating the heterogeneity of TAM metabolic features across tumor types and subsets and discuss the implications of these metabolic variations for TAM-mediated immunosuppression. Furthermore, we summarize the representative therapeutic agents targeting key metabolic nodes in TAMs. By integrating emerging insights into TAM metabolism and associated pharmacologic interventions, this review aims to identify key unanswered questions and provide a theoretical framework for developing precision immunotherapies that target TAM metabolic nodes without compromising anti-tumor immunity.

In this study, we designed a lignin-based nanocarrier system with dual-stimuli responsiveness to the acidic pH and elevated glutathione (GSH) levels in the tumor microenvironment, and doxorubicin (DOX) was loaded to develop a nanomedicine delivery platform for antitumor treatment. Under the optimized conditions, uniform lignin-based nanoparticles with a diameter of approximately 150 nm and well-controlled physicochemical properties were successfully prepared. In vitro release studies confirmed the selective drug release under simulated tumor conditions (pH 6.5, 10 mM GSH). Biological evaluation revealed that the drug-loaded nanoparticles exhibited potent cytotoxicity against 4T1 breast cancer cells, while maintaining over 85% viability in normal cells, indicating good biocompatibility. In 4T1 tumor-bearing mice, the engineered nanocarriers demonstrated significantly enhanced therapeutic efficacy, achieving 71.84% tumor growth inhibition compared to that of 58.78% with free DOX, along with reduced systemic toxicity. In summary, this study demonstrates the successful transformation of sustainable lignin into an efficient therapeutic platform via precise chemical modification, effectively combining biopolymer advantages with stimulus-triggered drug release for more promising and biodegradable nanocarriers for cancer therapy.

We report the discovery, structural elucidation, and first total synthesis of two unprecedented marine oxazole derivatives, PM100618 and PM110049, isolated from the Papua New Guinean sponge Rhabdastrella rowi. Both compounds exhibit potent in vitro cytotoxic activity at nanomolar concentrations. A highly convergent and efficient total synthesis of PM100618 and PM110049 was achieved in 22 and 21 steps, respectively (longest linear sequence: 15 steps) through the coupling of two complex fragments. This synthetic route provides ready access to these scarce natural products, enabling advanced pharmacological evaluation and mechanistic studies of this new class of marine-derived anticancer agents.

Phenylacetylglutamine (PAGln), a gut microbiota-derived metabolite, is associated with enhanced thrombosis. However, its impact on endothelial function and angiogenesis remains unclear. A murine hindlimb ischemia model was used to assess perfusion recovery. Human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation were evaluated in vitro. Gene set enrichment analysis (GSEA) was performed for pathway enrichment analyses. Furthermore, glycolytic flux and enzyme expression were measured. Lentiviral lactate dehydrogenase A (LDHA) overexpression was performed both in vitro and in vivo. Elevated PAGln impaired blood flow recovery and inhibited HUVEC proliferation, migration and tube formation. β-receptor blocker zenidolol was able to reverse the adverse effects. PAGln downregulated glycolytic pathways, reduced proton efflux, and suppressed LDHA expression and lactate production. LDHA overexpression rescued PAGln-induced angiogenic impairment. The gut metabolite PAGln may suppress angiogenesis of HUVEC by targeting the β-receptors, subseqeuently inhibiting LDHA expression.

Identify subgroups of oncology patients with distinct joint chemotherapy-induced nausea (CIN) AND morning fatigue profiles and distinct joint CIN AND evening fatigue profiles, as well as modifiable and non-modifiable risk factors.

Immune checkpoint inhibitors (ICIs) are effective for many cancers but often cause immune-related adverse events, particularly gastrointestinal (GI) complications such as colitis. Identifying risk factors for ICI colitis (CIC) could improve patient selection and discover potential mechanisms relevant to idiopathic inflammatory bowel disease (IBD). We aim to identify risk factors with a robust methodological approach in a large multi-center longitudinal cohort.

Hemorrhagic central nervous system (CNS) metastases are well recognized in melanoma yet seldom represent the initial manifestation, and fulminant, steroid-refractory hepatitis from immune checkpoint inhibitors (ICIs) remains exceedingly rare. Here, we present a 54-year-old man with no prior medical history who was brought to the emergency department with acute confusion and aphasia and was found to have a large right frontal hemorrhagic mass with midline shift. Urgent craniotomy and hematoma evacuation revealed high-grade melanoma, BRAF V600-negative. Imaging identified stage IV disease with pulmonary and hepatic metastases. He was started on ipilimumab and nivolumab combination therapy outpatient; however, treatment was held after 2 cycles due to marked transaminitis, and prednisone was initiated for presumed ICI-related hepatitis. Despite corticosteroids, liver function progressively worsened over the following weeks, which required a second hospitalization and culminated in fulminant liver failure and encephalopathy. High-dose methylprednisolone offered minimal improvement. Although second-line immunosuppressants were considered, rapid deterioration prompted initiation of tocilizumab. His hospitalization was complicated by multiorgan failure and radiographic progression of CNS metastases, and he ultimately transitioned to comfort care and died on hospital day 7. This case demonstrates hemorrhagic CNS disease at diagnosis alongside early, fulminant, steroid-refractory ICI hepatitis and highlights the need for heightened hepatic surveillance and early escalation of immunosuppression during dual checkpoint blockade.

IntroductionImmune checkpoint inhibitors (ICIs) are extensively utilized in lung cancer patients, with documented instances of ICIs-associated acute kidney injury (ICIs-AKI). This study aims to explore a model for early recognition of ICIs-AKI.MethodsThe study involved 413 adult lung cancer patients treated with ICIs at Ningbo No.2 Hospital between Sept. 1, 2021, and June 30, 2023. Patients were followed until death or Dec. 31, 2023, and categorized into ICIs-AKI or non-AKI groups. We employed univariate and multivariate logistic regression to identify risk factors, developed both logistic regression and Multilayer Perceptron (MLP) prediction models, and used Kaplan-Meier survival analysis to assess prognosis.ResultsThe study included 381 lung cancer patients receiving ICIs treatment after excluding 32 patients. ICIs-AKI occurred in 13.39% of cases, with a median onset time of [123 (63, 303)] days. Multivariable logistic analysis identified diabetes, proteinuria, extrarenal irAEs, diuretic use, and chemotherapy as significant risk factors (all P < 0.05), while higher baseline eGFR levels were protective (P < 0.05). Two prediction models were developed: logistic regression (AUC=0.877, sensitivity=0.922, specificity=0.726) and MLP (AUC=0.950, accuracy=0.843, precision=0.847). Survival analysis showed no difference in overall survival between ICIs-AKI and non-AKI groups (HR = 1.021, 95% CI = 0.629-1.659, P = 0.932; adjusted HR = 0.950, 95% CI = 0.558-1.616, P = 0.849). AKI to CKD progression incidence was 58.82%, with no significant difference in overall survival between CKD and non-CKD groups (P = 0.157).ConclusionThis study offers detailed insights into ICIs-AKI, including its rate, onset timing, risk factors, and clinical features. Approximately half of the affected patients experienced spontaneous renal function recovery. Both logistic regression and MLP models effectively predicted ICIs-AKI. Importantly, neither ICIs-AKI incidence nor renal function restoration correlated with patient mortality. These findings underscore the importance of early detection and management strategies.

A facile and effective strategy was developed to construct a highly dispersed carbon dot-based COF. The resulting CD-COF exhibited good crystallinity, superior water dispersibility, pH-responsive degradation behavior, and high photodynamic therapy activity. This study provides a promising strategy to fabricate water-dispersed COFs for highly efficient tumor ablation.

BACKGROUND Immune checkpoint inhibitors (ICIs) are widely used as first-line combination therapies for many cancers. However, ICIs are associated with an increased risk of graft rejection in patients requiring liver transplants, and the tumor response rate has yet to be determined. MATERIAL AND METHODS This retrospective study included liver transplant recipients who received ICIs for recurrent hepatocellular carcinoma. During ICI therapy, baseline immunosuppressant doses were maintained, with low-dose steroid treatments added when clinically indicated. RESULTS A total of 25 patients were included, with 12 receiving ICIs as first-line therapy, and 13 as second-line therapy. The median progression-free survival (PFS) was 4.93 months (95% CI, 2.33-28.63) and 7.20 months (3.80-32.47), respectively. One patient (4.0%) developed grade 2 hepatitis, and 2 (8%) experienced grade 3 gastrointestinal bleeding. Concurrent steroid use was associated with fewer immune-related adverse events (0% vs 30%, P=0.052) but showed a trend toward shorter PFS (HR=2.30, P=0.071). Two patients (8%) achieved complete remission, and 4 (16%) maintained disease control for more than 1 year. In multivariable analysis, recurrence within 1 year after transplantation was the only significant prognostic factor for PFS (HR=2.98, P=0.043). CONCLUSIONS Our findings suggest that ICIs can be administered after liver transplantation without reducing baseline immunosuppressant doses, potentially minimizing the risk of fatal allograft rejection while still allowing antitumor activity. These results should be interpreted cautiously, and larger studies are needed to define the safe and appropriate use of ICIs in this population.

Functionalized dendrimeric nanoparticles (BH40-PEG-F127-FA) were synthesized to develop a targeted delivery platform for combined therapeutic and imaging applications. Structural confirmation through FT-IR, 1H-NMR, 13C-NMR, and MALDI-TOF mass spectrometry verified the successful formation of the macromolecular architecture. The nanoparticles exhibited hydrodynamic sizes of 190-255 nm, while transmission electron microscopy revealed micellar structures ranging from 35 to 190 nm. The critical micelle concentration of the copolymer was determined as approximately 0.001 mg/mL. Thermal analyses demonstrated the stability of BH40-PEG and BH40-PEG-F127-FA. Gd2O3 and sphingosine kinase inhibitors (SKI-I/II) were incorporated using a supercritical CO2 method, and structural integrity after loading was confirmed by FT-IR and x-ray diffraction. Drug-release studies performed in phosphate-buffered saline (pH 6.7, 37°C) indicated a sustained release over 192 h. Cytotoxicity assays on A549 lung cancer cells and Beas-2B healthy epithelial cells revealed selective antiproliferative activity, while confocal microscopy demonstrated treatment-induced morphological alterations. Overall, BH40-PEG-F127-FA nanoparticles show strong potential as biocompatible carriers for targeted therapy and multimodal imaging.