Immune checkpoint inhibitors (ICIs) deliver prominent anti-tumor efficacy across multiple malignancies, yet ICI-associated myocarditis represents a life-threatening adverse event requiring standardized management. Updated from the 2022 version, these recommendations integrate up-to-date domestic and international real-world data and emerging evidence concerning bispecific antibody-related cardiac injury, thymic imaging grading, artificial intelligence-assisted early screening, and optimized second-line immunosuppressive regimens. These recommendations provide standardized practical guidance for prevention, early recognition and individualized intervention to improve patient outcomes.

11562 Background: Primary cardiac angiosarcoma (PCAS) is an exceedingly rare and lethal mesenchymal malignancy characterized by aggressive growth and high metastatic potential. Despite the use of taxane-based regimens, the prognosis remains dismal, with a historical median overall survival (mOS) of approximately 11 months. Given the highly vascular nature of PCAS, we hypothesized that integrating a multi-target anti-angiogenic TKI (anlotinib) with cytotoxic chemotherapy could synergistically improve outcomes. This study evaluated the efficacy and safety of anlotinib plus nab-paclitaxel and gemcitabine (AG) in advanced PCAS. Methods: We retrospectively analyzed patients with metastatic or unresectable PCAS treated at Zhongshan Hospital, Fudan University. The triplet regimen consisted of anlotinib (8-12 mg QD, days 1-14, q3w), nab-paclitaxel (200 mg), and gemcitabine (1000 mg/m²) on days 1 and 8 every 3 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), and safety (CTCAE v5.0). Survival outcomes were estimated using the Kaplan-Meier method and compared via log-rank tests. Results: A total of 24 patients were included, with a median age of 44 years. Most tumors (91.7%) originated in the right atrium, and 70.8% of patients received this regimen as first-line therapy. Efficacy: At a median follow-up of 31.4 months, the ORR was 62.5% and the DCR was 95.8%. Survival: The median PFS was 9.5 months (95% CI, 8.4-20.7). Notably, the median OS reached 24.9 months (95% CI, 15.2-NR), significantly exceeding historical benchmarks. Prognostic Indicators: Subgroup analysis identified liver metastasis (45.8%) as a significant negative prognostic factor for PFS (p = 0.018). Additionally, a numerical trend toward shorter survival was observed in patients with baseline D-dimer > 5 mg/dL (Median OS: 5.5 vs. 10.5 months; p = 0.428). Safety: Treatment-related adverse events (TRAEs) of any grade occurred in 95.8% of patients. Grade≥3 TRAEs (41.7%) were primarily hematological (neutropenia, thrombocytopenia) and were manageable via dose modification. No severe treatment-related cardiotoxicity was observed. Conclusions: The triplet combination of anlotinib and AG demonstrates unprecedented survival benefits and a manageable safety profile in advanced PCAS. With a mOS exceeding twice the historical data, this regimen represents a potent new treatment strategy. Liver involvement serves as a critical prognostic indicator for risk stratification, while the clinical significance of baseline D-dimer levels as a surrogate marker for tumor burden warrants further investigation in larger cohorts.

Increased matrix stiffness is a biomechanical feature of hepatocellular carcinoma (HCC) that functions as an important promoting factor driving tumor progression. Characterization of the mechanosensors and the underlying downstream mechanisms driving HCC could help identify potential treatment strategies. In this study, we developed a standard procedure for screening and identifying mechanosensors, revealing two HCC mechanosensors, SDC4 and PKD2. These two mechanosensory pathways collaboratively mediated matrix stiffness-promoted DNA damage repair. Specifically, SDC4 and PKD2 modulated matrix stiffness-increased BANF1 nuclear translocation through increasing PP2A assembly and activity. Subsequently, nuclear BANF1 promoted the formation of MRN complex and phosphorylation of its downstream effectors to enhance DNA damage repair. These findings not only expand the theoretical understanding of matrix stiffness-regulated DNA damage repair but also offer a screening/identification approach for mechanosensors in cancer.

Background: While N6-methyladenosine (m6A) modification is increasingly linked to tumorigenesis, its role in regulating lipid metabolism in rectal adenocarcinoma (READ) remains unclear. This study aims to investigate the molecular mechanism by which the m6A reader protein N6-methyladenosine RNA binding protein 1 (YTHDF1) facilitates the progression of READ by regulating Acyl-CoA synthetase long chain family member 3 (ACSL3) translation and influencing lipid metabolism. Methods: The Cancer Genome Atlas-READ database was used to compare the expression levels of YTHDF1 and ACSL3 in READ and normal tissues. Lentivirus-mediated knockdown and overexpression of YTHDF1 and ACSL3 were performed in the human READ cell line SW1463. Cellular phenotypes were evaluated through Cell Counting Kit-8 viability assays, colony formation and proliferation assays, flow cytometric cell cycle and apoptosis analyses, wound healing migration tests, and Transwell invasion experiments. Intracellular concentrations of cholesterol, triglycerides, and adenosine triphosphate were quantified with commercial assay kits. Molecular interactions between YTHDF1 and ACSL3 were examined using RNA immunoprecipitation, crosslinking immunoprecipitation, m6A immunoprecipitation, and polysome profiling assays. The in vivo function of YTHDF1 was assessed in a nude mouse xenograft model. Results: YTHDF1 was significantly upregulated in READ tissues. Its knockdown suppressed proliferative, migratory, invasive, and lipid synthetic activities in READ cells. ACSL3 was confirmed as a functional target of YTHDF1 bearing m6A modification. YTHDF1 facilitated ACSL3 protein synthesis in an m6A-dependent fashion. Exogenous ACSL3 expression rescued the tumor-suppressive effects caused by YTHDF1 silencing. Conclusions: YTHDF1 enhances ACSL3 translation in an m6A-dependent manner to promote lipid metabolism, thereby facilitating the progression of READ.

BACKGROUND:Immune checkpoint inhibitor-associated myocarditis (ICIAM) poses significant challenges for cancer immunotherapy, particularly regarding the safety and efficacy of immune checkpoint blockade (ICB) rechallenge. METHODS:The present study analyzed 23 cases of ICIAM by integrating longitudinal clinical data with single-cell RNA sequencing and T-cell receptor profiling of peripheral blood mononuclear cells (PBMCs) obtained from three representative patients before and after ICB rechallenge. The single-cell cohort comprised two patients who experienced recurrent irAEs upon rechallenge and one patient who did not develop recurrent irAEs. RESULTS:Among 12 patients (52%) who experienced recurrent irAEs upon rechallenge, myocarditis recurrence occurred in 8 cases, with most (88%) presenting as grade 1- significantly milder than initial episodes (p=0.046). Single-cell analysis revealed that the patient who did not develop recurrent irAEs exhibited a high proportion of effector CD8+ T cells with high TRAV19 expression (CD8 Teff TRAV19), a TCR Vα family associated with SARS-CoV-2 reactivity. In contrast, patients who experienced recurrent irAEs lacked this expanded population. Rechallenge during myocarditis course was associated with higher recurrent irAEs risk (OR=14.0, 95%CI:1.3-147.4, p=0.027). Despite recurrence, tumor response was preserved, with a median progression-free survival (mPFS) of 8.5 months and no significant outcome difference between patients with and without post-rechallenge irAEs. CONCLUSION:ICB rechallenge is feasible in selected ICIAM patients, with most recurrent myocarditis cases being milder. Our exploratory single-cell analysis reveals that a high proportion of CD8 Teff TRAV19 was present in the patient protected from recurrence but absent in those who relapsed, suggesting that pre-existing virus specific memory T cells may modulate recurrent irAEs risk via antigen-specific niche occupation. While limited by sample size, these findings generate the hypothesis that T-cell repertoire composition could inform patient selection for ICB rechallenge, a concept warranting validation in larger cohorts.

Chemotherapy and radiation reduce tumor burden but leave behind residual cells that survive via therapy-induced senescence (TIS). These cells constitute a latent reservoir fueling recurrence, yet strategies for their selective elimination are lacking. Here, we identify lysosomal ferrous iron accumulation as a conserved hallmark and actionable vulnerability of TIS tumor cells. Across diverse models, senescent tumor cells exhibit marked hypersensitivity to ferroptosis induction. In breast cancer PDX models, sequential ferroptosis induction following chemotherapy significantly delays recurrence, while dual inhibition of GPX4 and FSP1 produces durable, often complete, eradication of residual tumors without overt toxicity. Mechanistically, activation of the TFEB-HO-1 axis in TIS tumor cells drives ferrous iron accumulation, thereby priming cells for ferroptosis. Together, these findings establish ferrous iron accumulation as a defining feature of TIS and position ferroptosis induction as a potent senolytic strategy to eliminate therapyrefractory residual disease.

3564 Background: FOLFOXIRI combined with targeted therapy is recommended for metastatic colorectal cancer (mCRC) patients suitable for intensive treatment or conversion surgery. However, the combination of irinotecan liposome, oxaliplatin, fluorouracil (NALIRIFOX) in mCRC remains uninvestigated. This Phase I study aimed to determine the maximum tolerated dose (MTD) of irinotecan liposome in this combined therapy for mCRC. Methods: Patients with histologically confirmed and initially unresectable mCRC were enrolled. In the dose-escalation phase (Phase Ia), a 3+3 design was utilized. Eligible patients received fixed doses of oxaliplatin (85mg/m 2 ), fluorouracil (2400mg/m 2 ) and bevacizumab (5mg/kg), while the dose of irinotecan liposome was escalated starting from 60mg/m 2 . If a dose-limiting toxicity (DLT) occurs at 60mg/m 2 , the dose can be reduced to 50mg/m 2 . Toxicity was evaluated using Common Terminology Criteria for Adverse Events (CTCAE5.0). In the dose-expansion phase (Phase Ib), irinotecan liposome was administered at the recommended dose from Phase Ia. Based on the RAS/BRAF gene status, either bevacizumab or cetuximab was combined with NALIRIFOX. The safety and efficacy of the combination were further assessed in Phase Ib. Results: From March 2024 to March 2025, 9 patients in the dose-escalation phase and 64 patients in the dose-expansion phase were enrolled, included 48 males and 25 females with a median age of 57 years. The MTD of irinotecan liposome was determined to be 50mg/m². Identified DLTs included grade 3 diarrhea and febrile neutropenia. As of January 15, 2026, 65 patients had at least one tumor assessment. The objective response rate (ORR) was 81.5% and the disease control rate (DCR) was 100.0%. The median PFS was 12.3 months (95% CI 9.8-14.7). The rate of R0 resection was 12.3%. The most common ≥grade 3 treatment-related adverse events (TRAEs) were diarrhea (18.4%) and neutropenia (14.5%). Conclusions: Irinotecan liposome at a dose of 50 mg/m² in the NALIRIFOX regimen showed manageable safety and promising efficacy as first-line treatment for mCRC. Clinical trial information: NCT06225622 .

Cholangiocarcinoma (CCA), a malignant tumor, is typically challenging to detect early and often results in a poor prognosis. In recent years, research interest has grown in the potential application of immunotherapy for CCA treatment. T cells, as a crucial component of the immune system, play a significant role in immune surveillance and therapy for cholangiocarcinoma. This article provides a review of the research advancements concerning T cells in cholangiocarcinoma patients, including their distribution, functional status, and correlation with patient prognosis within the tumor microenvironment. It further discusses the potential applications and challenges of immunotherapy strategies targeting T cells in CCA treatment and anticipates future research directions. A more profound understanding of T cells' role in cholangiocarcinoma can guide the development of clinical treatment strategies, thereby enhancing patient survival rates and quality of life. Finally, we explored the potential risks and side effects of immunotherapy for T-cell cholangiocarcinoma.

BACKGROUND:The expression and prognostic predictive value of programmed death-ligand 2 (PD-L2) in patients undergoing radical gastric cancer (GC) surgery remains unclear. METHODS:PD-L2 expression in tumor cells (TC) and tumor-infiltrating immune cells (TIIC) was evaluated by immunohistochemistry. Kaplan-Meier and Cox models were used to evaluate the association of PD-L2 with disease-free survival (DFS) and overall survival (OS). RESULTS:This study included 299 patients and the average age was 63.76 ± 11.83 years, with 218 males (72.91%) and 81 females (27.09%). TC PD-L2 expression was significantly associated with poorer DFS (HR = 2.177, 95% CI 1.364-3.474, P = 0.001) and OS (HR = 1.943, 95% CI 1.191-3.169, P = 0.008). Multivariate analysis confirmed TC PD-L2 expression as an independent poor prognostic factor for DFS (HR = 2.121, 95% CI 1.325-3.393, P = 0.002) and OS (HR = 1.812, 95% CI 1.109-2.961, P = 0.018). PD-L2 in TIIC did not correlate with survival. Other poor prognostic factors included age ≥60, vascular invasion, advanced postoperative stage, and HER2 positivity. CONCLUSIONS:PD-L2 expression in TC is an independent prognostic biomarker in GC, linked to poorer DFS and OS, suggesting its potential for identifying high-risk patients for personalized therapies.

To develop and validate a machine learning framework combined with a nomogram for predicting recurrence after radical gastrectomy in patients with vascular and neural invasion. Machine learning models, including Random Survival Forests, Decision Survival Tree, Extreme Gradient Boosting, and a nomogram, were developed and assessed for their ability to predict recurrence-free survival in patients who underwent radical gastrectomy for non-metastatic gastric cancer with "double invasion". A total of 559 patients were included in the study, and the machine-learning models demonstrated higher c-index values than the nomogram. The Random Survival Forests model had the highest c-index of 0.791, followed by Extreme Gradient Boosting (0.788) and Decision Survival Tree (0.728). Our refined nomogram harnessed the power of the Random Survival Forests algorithm to weave together the critical influence of nine variables: patient gender, age, the tally of positive lymph nodes, the surgical approach to gastrectomy, the tumor's positional characteristics, and the molecular biomarker expression profiles, including CD56 and FHIT, along with ki67 levels and the tumor's maximum diameter. All models showed good calibration with low integrated Brier scores (< 0.1), although there was calibration drift over time, particularly in the traditional nomogram model. DCA showed an incremental net benefit from all machine learning models compared with conventional models currently used in practice. Random Survival Forests have surpassed traditional machine learning and nomograms in predictive accuracy, yet nomograms remain vital for identifying high-risk patients and guiding postoperative care. Combining nomograms with advanced machine learning in a hybrid model enhances patient care, provides critical insights, and supports informed clinical decisions for gastric cancer cases with "double invasion".

Apart from the classic features, it is almost unknown whether there exist other new pathological features during pre-metastatic niche formation in hepatocellular carcinoma (HCC). Our previous works have highlighted the contribution of increased matrix stiffness to lung pre-metastatic niche formation and metastasis in HCC. However, whether increased matrix stiffness influences glucose metabolism and supply of lung pre-metastatic niche remains largely unclear. Here we uncover the underlying mechanism by which matrix stiffness-tuned exosomal miRNAs as the major contributor modulate glucose enrichment during lung pre-metastatic niche formation through decreasing the glucose uptake and consumption of lung fibroblasts and increasing angiogenesis and vascular permeability. Our findings suggest that glucose enrichment, a new characteristic of the lung pre-metastatic niche triggered by matrix stiffness-tuned exosomal miRNAs, is essential for the colonization and survival of metastatic tumor cells, as well as subsequent metastatic foci growth.

Representativeness of Study Participants

BACKGROUND:Pancreatic cancer (PC) is often diagnosed at advanced stages, limiting surgical options. There is no standardized treatment for second-line or beyond therapies, necessitating alternative treatments. This study evaluates the efficacy and safety of anlotinib combined with chemotherapy in advanced PC patients receiving second-line or subsequent treatments. METHODS:A retrospective analysis of 68 advanced PC patients was conducted. Twenty-six patients treated with anlotinib and chemotherapy were compared to 42 controls who received chemotherapy only. Demographic data, efficacy, survival, and adverse reactions were analyzed. RESULTS:In the anlotinib group, the therapeutic responses were as follows: Complete Response: 0, Partial Response: 2 (7.7%), Stable Disease: 13 (50.0%), and Progressive Disease: 11 (42.3%), the Objective Remission Rate was 7.7%, and the Disease Control Rate was 57.7%. The median Progression-Free Survival was 4.5 months. The Overall Survival was significantly longer in the anlotinib group compared to controls. Common adverse reactions included fatigue, bone marrow suppression, and hypertension, mostly grade 1-3. The potential toxicity and cumulative toxicity of long-term use is hand-foot syndrome, hypothyroidism and hypertension. CONCLUSION:The data generated suggest that anlotinib combined with chemotherapy may be an effective and tolerable option for second-line and subsequent treatment of advanced PC.

Background Although the contribution of matrix stiffness to aggravating the malignant features of HCC cells has been well documented, the effects of matrix stiffness on chemoradiotherapy resistance and its underlying mechanism remain largely elusive.Methods To delineate the role of matrix stiffness in HCC progression, we engineered novel in vivo animal models with defined liver stiffness and a complementary tunable hydrogel culture system. This integrated approach enabled a comprehensive investigation into how biomechanical cues modulate HCC cell proliferation and DNA repair both in vitro and in vivo.Results High stiffness stimulation noticeably enhanced cell proliferation and cell survival from DNA damage through changing the expression and distribution of metabolic enzyme PFKFB3. Specifically, high stiffness stimulation prominently suppressed PFKFB3 ubiquitination by downregulating E3 ubiquitin ligase NEDD4, and then increased the stability of PFKFB3 protein to enhance glycolysis, ultimately promoted HCC growth. Meanwhile, high matrix stiffness stimulation also effectively strengthened the DNA damage repair ability of irradiated HCC cells, and PFKFB3 nuclear translocation mediated in matrix stiffness-regulated DNA damage repair by interacting with Ku70.Conclusions Our results delineate a PFKFB3-mediated pathway that underpins how increased matrix stiffness potentiates HCC growth and compromises radiotherapy efficacy. These findings not only highlight the contribution of matrix stiffness to tumor growth and DNA damage repair in HCC, but also disclose a previously unidentified nonmetabolic function of PFKFB3.Key points Increased matrix stiffness significantly promoted glycolysis in HCC cells via upregulating PFKFB3 expression. High stiffness stimulation suppressed PFKFB3 ubiquitination by downregulating E3 ubiquitin ligase NEDD4 expression. PFKFB3 participated in DNA damage repair by translocating into nuclear and interacting with Ku70, which strengthened by matrix stiffness.

Background Intimal sarcoma (IS) represents a rare and aggressive subtype of sarcoma predominantly impacting the heart and major blood vessels, posing significant challenges in both diagnosis and surgical intervention. Despite the administration of anthracycline-based regimens in advanced stages, the prognosis remains unfavorable. Methods This study aims to analyze the clinical characteristics of the disease and to evaluate the efficacy and safety of various treatment modalities. Results The findings underscores the limited therapeutic options, which generally encompass anthracyclines, taxanes, and anti-angiogenic therapies, suggesting the feasibility of anti-angiogenic therapy and CDK4/6 inhibitors, thereby contributing to an enhanced understanding and management of this uncommon malignancy. Conclusions IS has a high postoperative recurrence rate, and adjuvant therapy may be beneficial. Anti-angiogenic therapy shows efficacy with low cardiovascular risk, and CDK4/6 inhibitors are also effective.

Tumor‐associated macrophages (TAMs) are one of the most abundant immune cells in solid tumors and play a critical role in tumor progression. This study found that the expression of LIM domain‐only protein 7 (LMO7) in TAMs is associated with poor patient survival. LMO7 deficiency significantly inhibited tumor growth and increased the accumulation of antitumor TAMs and CD8 + T cells. Specifically, single‐cell RNA sequencing (scRNA‐seq) reveals that LMO7‐deficient TAMs undergo an antitumor reprogramming, characterized by upregulated expression of pro‐inflammatory and phagocytosis‐related genes. Notably, LMO7 deficiency enhances immune‐mediated tumor confinement by regulating the phagocytic activity of TAMs. Mechanistically, LMO7 inhibits TAM phagocytosis by promoting the lysine 48‐linked polyubiquitination at lysine 45 of the β chain of the phagocytic receptor low‐density lipoprotein receptor‐related protein 1 (LRP1), leading to degradation via the ubiquitin‐proteasome system. Furthermore, combined targeting of LMO7 deficiency and SIRPα blockade demonstrates synergistic antitumor efficacy. Collectively, these findings demonstrate the critical role of LMO7 in orchestrating TAM phagocytosis and suggest that LMO7 inhibition is a promising drug target to enhance cancer immunotherapy.

Growing evidence has suggested that increased matrix stiffness can significantly strengthen the malignant characteristics of hepatocellular carcinoma (HCC) cells. However, whether and how increased matrix stiffness regulates the formation of invadopodia in HCC cells remain largely unknown. In the study, we developed different experimental systems in vitro and in vivo to explore the effects of matrix stiffness on the formation of invadopodia and its relevant molecular mechanism. Our results demonstrated that increased matrix stiffness remarkably augmented the migration and invasion abilities of HCC cells, upregulated the expressions of invadopodia-associated genes and enhanced the number of invadopodia. Two regulatory pathways contribute to matrix stiffness-driven invadopodia formation together in HCC cells, including direct triggering invadopodia formation through activating integrin β1 or Piezo1/ FAK/Src/Arg/cortactin pathway, and indirect stimulating invadopodia formation through improving EGF production to activate EGFR/Src/Arg/cortactin pathway. Src was identified as the common hub molecule of two synergistic regulatory pathways. Simultaneously, activation of integrin β1/RhoA/ROCK1/MLC2 and Piezo1/Ca2+/MLCK/MLC2 pathways mediate matrix stiffness-reinforced cell migration. This study uncovers a new mechanism by which mechanosensory pathway and biochemical signal pathway synergistically regulate the formation of invadopodia in HCC cells.

The crucial role of gut microbiota in shaping immunotherapy outcomes has prompted investigations into potential modulators. Here we show that oral administration of acarbose significantly increases the anti-tumour response to anti-PD-1 therapy in female tumour-bearing mice. Acarbose modulates the gut microbiota composition and tryptophan metabolism, thereby contributing to changes in chemokine expression and increased T cell infiltration within tumours. We identify CD8+ T cells as pivotal components determining the efficacy of the combined therapy. Further experiments reveal that acarbose promotes CD8+ T cell recruitment through the CXCL10-CXCR3 pathway. Faecal microbiota transplantation and gut microbiota depletion assays indicate that the effects of acarbose are dependent on the gut microbiota. Specifically, acarbose enhances the efficacy of anti-PD-1 therapy via the tryptophan catabolite indoleacetate, which promotes CXCL10 expression and thus facilitates CD8+ T cell recruitment, sensitizing tumours to anti-PD-1 therapy. The bacterial species Bifidobacterium infantis, which is enriched by acarbose, also improves response to anti-PD-1 therapy. Together, our study endorses the potential combination of acarbose and anti-PD-1 for cancer immunotherapy.