Figure S8. In vivo biosafety evaluation of JS-201 and summary of combination therapy.

Radiation-induced lung injury (RILI), including radiation pneumonitis (RP) and radiation-induced pulmonary fibrosis (RIPF), represents a major dose-limiting complication in thoracic radiotherapy. Acute RP constrains radiotherapy implementation, while RIPF causes irreversible pulmonary dysfunction. During ionizing radiation, the STING pathway is upregulated, and oxidative stress is induced in macrophages, promoting acute RP and resulting in late RIPF. In this study, an inhalable ferrous nanozyme encapsulating rosmarinic acid, termed FeRAzyme, was developed to address RILI induced by radiotherapy. Rosmarinic acid was rationally selected through molecular docking and dynamics simulations, revealing its non-covalent binding to STING at residues Ser243-Tyr245-Leu259-Glu260-Asn211, which blocks STING phosphorylation. After screening of a metal-based nanozyme library, FeRAzyme showed remarkable catalase- and superoxide dismutase-mimetic activities, efficiently scavenging reactive oxygen species and thus attenuating radiation-induced oxidative damage. Administered via inhalation, FeRAzyme suppressed STING phosphorylation and alleviated oxidative stress in macrophages, thus inhibiting proinflammatory cytokine secretion. Both in vitro and in vivo studies demonstrated that FeRAzyme effectively restored macrophage homeostasis and ameliorated both acute RP and myofibroblast activation without systemic toxicity. This work establishes a dual-functional STING-inhibitory nanozyme strategy for mitigating RILI, offering a promising approach for radioprotection in thoracic cancer radiotherapy.

Objective: Visceral adiposity has been implicated in carcinogenesis through chronic inflammation, insulin resistance, and lipid dysregulation, whereas body mass index (BMI) does not capture fat distribution. The Visceral Adiposity Index (VAI)-combining waist circumference, BMI, triglycerides, and high-density lipoprotein-cholesterol (HDL-C)-serves as a surrogate of visceral fat function, but its value for cancer risk prediction is unclear. We aimed to evaluate the association between VAI and cancer prevalence in U.S. adults using NHANES 1999-2020, assess independence from BMI, characterize subgroup and dose-response patterns, and conduct prespecified exploratory site-specific analyses. Methods:A total of 20,699 adults aged >= 20 years were included after excluding participants with missing data. The primary outcome was a self-reported history of physician-diagnosed cancer, with the exclusion of non-melanoma skin cancers-such as basal cell carcinoma and squamous cell carcinoma-due to their typically indolent behavior and minimal epidemiological impact. Importantly, melanoma cases were included in the analysis. VAI was analyzed both as a continuous variable and in quartile-based categories (<1.0, 1.0-<2.0, 2.0-<3.0, and >= 3.0). Weighted logistic regression models were constructed with progressive adjustment for demographic, lifestyle, and metabolic covariates (e.g., hypertension, diabetes). Restricted cubic spline (RCS) analyses were performed to assess the dose-response relationship between VAI and cancer, and interaction analyses were conducted across subgroups defined by sex, age, BMI, and hypertension status. Results: In the unadjusted model, each one-unit increase in VAI was associated with significantly higher odds of cancer (OR = 1.019; 95% CI: 1.003-1.035; p = 0.019). Participants in the highest VAI category (>= 3.0) had approximately threefold increased odds of cancer compared to those in the lowest category (<1.0) (OR = 3.04; p < 0.001). After stepwise adjustment for demographic and lifestyle factors, the association attenuated; in our prespecified primary model that excluded BMI and hyperlipidemia to avoid overadjustment, the association remained statistically significant (OR = 1.024; 95% CI: 1.004-1.045; p = 0.021), indicating that higher VAI was independently associated with cancer prevalence. RCS analysis suggested a weak, approximately linear increase in cancer prevalence odds with increasing VAI, without a clear threshold effect; the overall association was statistically significant (p = 0.0428), and the test for nonlinearity showed borderline significance (p = 0.0540). Subgroup analyses showed a consistent pattern across most strata, except for a borderline significant interaction by hypertension status (p = 0.044), with a stronger association in individuals without hypertension. In pre-specified site-specific analyses, no individual cancer type demonstrated an independent positive association with VAI after full adjustment; intermediate VAI levels were inversely associated with cervical cancer, a counterintuitive finding that warrants cautious interpretation given limited case counts. Conclusions: Higher VAI levels were associated with increased cancer prevalence; however, the strength of the association diminished after controlling for traditional obesity metrics. These findings suggest that VAI may offer limited independent predictive value for cancer risk beyond BMI. Further prospective and mechanistic studies are warranted to establish causal relationships and evaluate the utility of VAI in identifying high-risk subpopulations.

PURPOSE:Antibody-drug conjugate (ADC) targeting human epidermal growth factor receptor 2 (HER2) could be a promising strategy for HER2-expressing gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJ) and colorectal cancer (CRC). We conducted a phase I trial to assess trastuzumab rezetecan, a novel HER2-targeted ADC, in HER2-expressing advanced GC/GEJ and CRC. METHODS:Patients with HER2-expressing advanced GC/GEJ and CRC whose disease progressed on and/or had no available/applicable standard treatment were enrolled. Patients were intravenously given trastuzumab rezetecan at 3.2, 4.8, 6.4, and 8.0 mg/kg (once every 3 weeks) in an i3+3 dose-escalation scheme, followed by pharmacokinetics expansion at selected doses and then clinical expansion. The primary end points were dose-limiting toxicity (DLT) and safety. RESULTS:Between March 30, 2021, and August 1, 2023, 100 patients were enrolled (57 with GC/GEJ and 43 with CRC). One DLT occurred in the 8.0 mg/kg dose cohort. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 66 (66.0%) patients. Only 5 (5.0%) patients discontinued treatment because of TRAEs. In HER2-positive GC/GEJ (n = 40), trastuzumab rezetecan achieved an objective response rate (ORR) of 45.0%, a median progression-free survival (PFS) of 9.0 months (95% CI, 7.0 to 11.3), and a median overall survival (OS) of 16.3 months (95% CI, 12.4 to not reached [NR]). In GC/GEJ with HER2 immunohistochemical 2+ and in situ hybridization-negative (n = 12), trastuzumab rezetecan had an ORR of 25.0%, a median PFS of 12.2 months (95% CI, 2.8 to 14.0), and an immature median OS. In HER2-positive CRC (n = 37), trastuzumab rezetecan had an ORR of 40.5%, a median PFS of 9.5 months (95% CI, 7.3 to 11.2), and a median OS of 22.7 months (95% CI, 17.5 to NR). CONCLUSION:Trastuzumab rezetecan showed tolerable safety and preliminary efficacy in HER2-expressing advanced GC/GEJ and CRC.

LBA3509 Background: The BRAF V600E mutation present in approximately 10% of metastatic colorectal cancer (mCRC) cases, confers a poor prognosis with limited response to chemotherapy. Tunlametinib is a novel, oral, high-potent MEK1/2 inhibitor. Synergistic effect of tunlametinib with vemurafenib was seen in BRAF mutant non-small cell lung cancer and mCRC in the previously published phase I trial (NCT03781219.). Based on promising Phase I/II data, we have this BRAF/MEK inhibitor dual-target regimen to advance to a Phase III randomized controlled trial in this population, addressing a significant unmet need. Methods: This randomized, open-label, phase III trial (NCT06008119) enrolled patients. with BRAF V600E–mutant mCRC after ≥1 prior line of systemic therapy. Patients were randomized 2:1 to tunlametinib (12 mg BID) + vemurafenib (720 mg BID) (T+V) or investigator's choice of therapy (control). A prespecified crossover from the control to the experimental arm is allowed upon IRC-confirmed disease progression. The primary endpoint is progression-free survival (PFS) assessed by a blinded Independent Review Committee per RECIST v1.1. Secondary endpoints include overall survival (OS), objective response rate (ORR), and safety. The primary endpoint PFS analysis will use a stratified log-rank test, with the hazard ratio (HR) and its 95% confidence interval estimated using a Cox proportional hazards model. Results: As of the data cutoff date for this analysis (March 5, 2026), the full analysis set included 157 patients (105 T+V, 52 control). Based on investigator assessment (IRC assessment ongoing), median PFS was significantly prolonged with T+V versus control (4.2 months vs. 1.5 months; HR 0.374; 95% CI 0.252–0.555; P < 0.001). The ORR was 37.1% (95% CI 27.9–47.1) in the T+V group versus 7.7% (95% CI 2.1–18.5) in the control group. P＜0.0001. DCR was 81.9% versus 38.5% (P < 0.0001), respectively. OS data was immature. Treatment-related grade≥3 adverse events (TRAEs) occurred in 62.0% vs 44.2% of patients, Permanent treatment discontinuation due to TRAEs occurred in 0.9% and 3.8%, respectively. Safety was consistent with that known for each agent. Conclusions: This is the first phase III randomized controlled trial to demonstrate that a BRAF/MEK inhibitor combination (tunlametinib plus vemurafenib) significantly improves PFS and ORR compared with conventional chemotherapy-based regimens in previously treated BRAF V600E–mutant mCRC, with a manageable safety profile and the added benefit of a convenient all-oral regimen. Clinical trial information: NCT06008119 .

Supportive care in cancer (SCC), which encompasses the management of symptoms and treatment-related adverse effects, as well as the promotion of physical and psychological well-being throughout the whole course of treatment into follow-up of survivors, can significantly improve the quality of life and clinical outcomes of cancer patients. Over the past decade, substantial progress has been achieved in SCC-related clinical research globally. However, development and implementation of SCC in China still face considerable challenges, largely attributable to regional disparities in medical resources, limited financial support, and sociocultural factors. This comprehensive review delineates the current state of SCC in China based on a nationwide cross-sectional survey, highlighting the unmet needs of cancer patients, survivors, and healthcare providers. Key issues included insufficient social and financial support, suboptimal symptom management, inadequate patient education, and limited use of electronic patient-reported outcomes (ePROs). These findings underscore an urgent need to develop standardized protocols, enhance multidisciplinary collaboration, and promote digital health tools to improve the application and quality of SCC in China.

3114 Background: Molecular profiling of cholangiocarcinoma (CCA) is highly recommended to guide access to targeted therapies such as FGFR2 inhibitors. 3HP-2827 is a highly selective and potent FGFR2 inhibitor targeting FGFR2 alterations. Here we report the findings of 3HP-2827 in advanced solid tumors harboring FGFR2 alterations. Methods: This is a phase I/II study to evaluate the safety, tolerability, PK, and preliminary efficacy of 3HP-2827 in pts with advanced solid tumors harboring FGFR2 alterations. Pts failed to standard therapy with/without prior pan-FGFR inhibitor (FGFRi) are eligible for enrollment. Bayesian Optimal Interval (BOIN) and back filling design were employed in the dose-escalation stage of phase I, followed with the expansion stage. Treatment-related adverse events (TRAEs), PK, and anti-tumor activity (RECIST v1.1) were assessed. Results: As of Jan 8, 2026, a total of 52 pts (46 with CCA, 6 with others) were enrolled from 12 centers, received 3HP-2827 at doses of 60-180 mg once daily (QD), including 42 with FGFR2 fusion/rearrangement (f/r), 6 with FGFR2 mutation. 19 pts (36.5%) had prior FGFRi. No dose-limiting toxicities (DLTs) were observed at the dose levels of 60 mg, 120 mg, 180 mg QD. 3HP-2827 had favorable PK with doses≥120 mg QD providing FGFR2 occupancy＞90%. The most common TRAEs were FGFR2 on-target toxicities including dry mouth (69.2%, G3 1.9%), nail toxicity (67.3%, G3 3.8%), stomatitis (50%, G3 3.8%), dry eyes (26.9%, G3 1.9%), PPE (19.2%, G3 3.8%). 12 pts (23.1%) experienced at least one G3/G4 TRAE and no G5 TRAEs occurred. 7 pts (13.5%) experienced at least one serious adverse event, 4 (7.7%) of them were considered related to 3HP-2827. No discontinued treatment or death due to TRAEs. Anti-tumor activities were observed from 60 mg QD. Among 15 CCA pts (FGFR2 f/r, FGFRi-naive) who had at least one post-treatment tumor assessment, objective response rate (ORR) was 80% (95% CI: 51.9, 95.7), and disease control rate (DCR) was 100% (95% CI: 78.2, 100). The ORR and DCR in 15 CCA pts (FGFR2 f/r, FGFRi-refractory) was 26.7% (95% CI: 7.8, 55.1) and 86.7% (95% CI: 59.5, 98.3). The ORR and DCR in 4 advanced solid tumor pts (FGFR2 mutation, FGFRi-naive) was 75% (95% CI: 19.4, 99.4) and 100% (95% CI: 39.8, 100). Conclusions: 3HP-2827 was found to be safe and tolerable, with encouraging anti-tumor activity observed in pts with FGFR2 alterations. Further clinical efficacy will be explored in the expansion stage and phase II stage. Clinical trial information: NCT06378593 .

Supplementary Table S1. Markers for cell annotation.

4176 Background: Extrapulmonary neuroendocrine carcinoma (EP-NEC) is a poorly differentiated and highly aggressive malignancy with poor prognosis. Platinum (cisplatin or carboplatin) plus etoposide (EC/EP) remains the standard first-line regimen. However, clinical outcomes are suboptimal, highlighting the need for more effective strategies. Camrelizumab is a programmed cell death-1 (PD-1) inhibitor, and apatinib is a vascular endothelial growth factor receptor-2 (VEGFR2) inhibitor. Both have demonstrated antitumor activity in multiple solid tumors. Therefore, we investigated a sequential regimen consisting of induction EC/EP plus camrelizumab followed by maintenance camrelizumab plus apatinib in treatment-naive patients with advanced or metastatic EP-NEC. Methods: This multicenter, single-arm trial enrolled patients with previously untreated advanced or metastatic EP-NEC. Patients received 4–6 cycles of induction therapy with cisplatin (25 mg/m² iv, d1-3, q3w) or carboplatin (AUC = 5 iv, d1, q3w) plus etoposide (100 mg/m² iv, d1-3, q3w) in combination with camrelizumab (200 mg iv, d1, q3w). Patients without disease progression received maintenance camrelizumab (200 mg iv, q3w) plus apatinib (250 mg, qd) until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Tumor response was assessed every 6 weeks per RECIST v1.1. The trial is registered on ClinicalTrials.gov, NCT05142865. Results: As of January 2026, 30 patients were enrolled (median age of 59.5 years, range 30–73), and all 30 patients were evaluable for efficacy. The ORR was 66.7% and the DCR was 83.3%. Median PFS was 9.87 months (95% CI, 6.23–NA). Median OS was not reached, and the 1-year OS rate was 74.6%. All patients experienced adverse events (AEs), with grade ≥3 AEs observed in 43.3% (13/30). Grade ≥3 AEs were mainly hematologic toxicities, including anemia (13.3%), neutropenia (13.3%) and thrombocytopenia (13.3%). Common non-hematologic AEs included elevated transaminases (43.3%), mainly grade 1–2, with grade ≥3 events in 10.0%. Conclusions: Induction EC/EP plus camrelizumab followed by maintenance camrelizumab plus apatinib showed encouraging activity and manageable safety in treatment-naive advanced or metastatic EP-NEC. Further studies are warranted to confirm these findings. Clinical trial information: NCT05142865 .

e15617 Background: Microsatellite stable (MSS) colorectal cancer (CRC) with unresectable liver metastases has limited effective third-line options. This study evaluated the efficacy and safety of transarterial chemoembolization/ hepatic arterial infusion chemotherapy (TACE/HAIC) combined with bevacizumab and tislelizumab in this setting. Methods: This single-center, prospective, observational study enrolled 21 patients with MSS CRC and unresectable liver metastases who failed at least two prior systemic therapies. One patient was excluded per protocol, leaving 20 evaluable patients. All received at least one cycle of TACE/HAIC combined with bevacizumab and tislelizumab. Primary endpoints was overall response rate(ORR) after 1 month of receiving the first combination therapy. Secondary endpoints included progression-free survival (PFS) , overall survival (OS), disease control rate (DCR), safety, and exploration of predictive biomarkers. Results: After the first efficacy assessment, the DCR was 70% (14/20 patients with stable disease, SD). No complete or partial responses were observed. The 6-month and 12-month PFS rates were 68.0% and 42.0%, respectively. Median PFS was 7.0 months and OS were 12.0 months (OS data immature, follow-up ongoing). Patients with < 2 extrahepatic metastatic sites had significantly longer PFS (6.5 vs. 3.2 months, P = 0.03). Grade ≥3 adverse events occurred in 29.4% of patients, primarily neutropenia (11.8%), hypertension (8.8%), and liver dysfunction (5.9%), with no treatment-related deaths. Exploratory biomarker analysis suggested that lower baseline BMI (< 24 kg/m²) was associated with better outcomes (P < 0.05), and a greater decrease in absolute lymphocyte count (ALC) after treatment correlated with progressive disease (PD). Conclusions: The combination of TACE/HAIC, bevacizumab, and tislelizumab demonstrated promising disease control and survival benefit with a manageable safety profile as a third-line therapy for MSS CRC with unresectable liver metastases. Baseline BMI and extrahepatic metastatic burden may help identify patients more likely to benefit. Further studies are warranted to optimize the regimen and validate predictive biomarkers. Clinical trial information: ChiCTR2500101315.

Background and purpose: Colorectal cancer (CRC) is one of the most prevalent and lethal malignancies worldwide, with distant metastasis—particularly to the liver—representing the primary cause of poor prognosis. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of CRC progression, yet the mechanisms by which they modulate G protein signaling during hepatic metastasis remain unclear. This study aimed to determine the role of the lncRNA SNHG5 in CRC liver metastasis and to explore whether G protein–related mechanisms are involved in this process. Methods: We established murine MC38 CRC sublines with distinct metastatic capacities (F0 and F3) and performed RNA sequencing to identify key lncRNAs. Biotin-labeled RNA pull-down coupled with mass spectrometry was used to identify SNHG5-interacting proteins. The SNHG5–GNB2 interaction was validated using RIP, RNA-FISH, and Western blot analyses. Functional rescue assays, in vivo liver metastasis models, and Wnt pathway activity measurements were conducted to delineate downstream effects. Public transcriptomic datasets from GEO and TCGA were used to assess the expression patterns and prognostic relevance of SNHG5 and GNB2 in CRC and metastatic lesions. Results: SNHG5 was significantly upregulated in the highly metastatic F3 subline and predominantly localized in the cytoplasm. Pull-down and proteomic analysis identified GNB2, a classical G protein β-subunit, as a direct binding partner of SNHG5. Functionally, SNHG5 promoted cell proliferation, migration, epithelial–mesenchymal transition (EMT), and suppressed apoptosis, while GNB2 overexpression partially rescued the tumor-suppressive phenotypes induced by SNHG5 silencing. Mechanistically, the SNHG5–GNB2 axis enhanced Wnt/β-catenin signaling via increased p-GSK3β and β-catenin levels, thereby driving EMT. Transcriptomic analyses further revealed that GNB2 is upregulated in CRC and liver metastases and is associated with poor prognosis. Multi-omics data suggested additional roles for this axis in immune evasion, metabolic reprogramming, and remodeling of the metastatic microenvironment. Conclusion: This study provides the first evidence that SNHG5 promotes CRC liver metastasis through direct interaction with GNB2 and subsequent activation of the Wnt/β-catenin pathway. The SNHG5–GNB2 axis orchestrates a multilayered regulatory network that integrates EMT induction, immune suppression, and metabolic adaptation, highlighting its potential as a mechanistic driver and therapeutic target in metastatic CRC.

Protein S-palmitoylation, the reversible thioesterification of cysteine side chains, is emerging as a druggable post-translational modification that couples membrane topology to oncogenic, metabolic, immune, and epigenetic networks in cancer. ZDHHC palmitoyltransferases and depalmitoylating enzymes, including acyl-protein thioesterases and palmitoyl-protein thioesterase 1, constitute a dynamic circuitry that governs the localization, stability, and signaling competence of key regulators of tumor growth, metabolic adaptation, and immune phenotype. Here, we synthesize recent structural and chemical biology advances that clarify how human ZDHHC enzymes achieve acyl-chain recognition and substrate engagement. Structural studies show that these enzymes adopt a four-transmembrane, "tent-like" fold, in which the helices create a membrane-embedded cavity for acyl-chain accommodation. We also discuss how ankyrin-repeat domains and accessory partners shape substrate recruitment and subcellular localization, and we highlight emerging high-throughput platforms that enable quantitative profiling of isoform- and site-selective modulators. We then discuss how ZDHHC-substrate circuits rewire canonical growth-factor signaling and epithelial-mesenchymal transition programs, metabolic and ferroptotic control nodes, innate immune sensing, and chromatin-linked regulation. These convergent mechanisms position ZDHHC-mediated S-palmitoylation as a context-dependent regulator of tumor progression, therapy response, ferroptosis sensitivity, and immune phenotype. Finally, we outline a translational framework encompassing clinical-stage PPT1 inhibitors, selective ABHD17 blockade, emerging ZDHHC modulators, substrate-competitive strategies targeting checkpoint palmitoylation, and selected comparator approaches affecting Wnt and Hedgehog ligand lipidation. Current evidence positions ZDHHC-mediated S-palmitoylation as a regulatory layer with potential biomarker and therapeutic relevance; however, not all reported ZDHHC-substrate associations carry equivalent evidentiary weight. Mechanisms supported by convergent site-directed, genetic, biochemical, functional, and in vivo evidence should be distinguished from associations inferred mainly from expression profiling, overexpression systems, single-model observations, or broad pharmacological perturbation. Clinical translation remains preliminary and is constrained by isoform selectivity, substrate redundancy, incomplete pharmacodynamic read-outs, and the absence of validated biomarker-guided patient stratification.

BACKGROUND:Pancreatic ductal adenocarcinoma is a malignancy characterized by profound immunosuppression and universal resistance to immunotherapy. The complex tumor microenvironment is a critical determinant of therapeutic failure. The chemokine C-X-C motif chemokine ligand 11 (CXCL11) exerts dual immunomodulatory roles in various tumors; however, its expression pattern, clinical significance, and molecular mechanisms in pancreatic cancer remain unclear. METHODS:This study integrated clinical cohort analysis, tissue microarray, transcriptomic sequencing, and in vitro functional experiments. Immunohistochemistry and multiplex immunofluorescence were used to analyze CXCL11 expression and its spatial relationship with immune cell infiltration. Transcriptomic sequencing was performed to identify differentially expressed genes after CXCL11 knockdown, followed by pathway enrichment analysis. CXCL11 knockdown and overexpression models were established in Panc02 and SW1990 cell lines, and western blotting was used to verify the regulatory effects on the nuclear factor kappa-B (NF-κB) signaling pathway and downstream CC motif chemokine ligand 2 (CCL2) expression. RESULTS:CXCL11 expression was higher in paratumor tissues than in tumor tissues of pancreatic cancer, and its high expression was significantly associated with shortened overall survival and more aggressive pathological features. Co-enrichement of CXCL11 with immunosuppressive markers such as CD163, CD11b, and programmed death-ligand 1 in paratumoral regions suggests its involvement in forming a spatially heterogeneous immunosuppressive barrier. Tissue-level analysis revealed a significant positive correlation between CXCL11 expression and the M2 macrophage marker CD163, as well as the myeloid-derived suppressor cell marker CD11b. Transcriptomic and functional experiments confirmed that CXCL11 activates the NF-κB signaling pathway and upregulates CCL2 expression. Tissue microarray further validated their positive correlations at the protein level. CONCLUSIONS:CXCL11 plays a pro-tumorigenic role in pancreatic cancer, with high expression levels predicting poor prognosis. By activating the NF-κB signaling pathway to upregulate CCL2, CXCL11 drives the "CXCL11-NF-κB-CCL2″ signaling axis, which, together with its enrichment in paratumoral regions, promotes the recruitment and activation of immunosuppressive cells and forms a functional immunosuppressive barrier at the invasive front. This provides a mechanistic explanation for immunotherapeutic resistance in pancreatic cancer and suggests CXCL11 and its related pathways as potential therapeutic targets.

SYS6010 is an antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). We report the results of a phase 1 trial (ChiCTR2300072141) of SYS6010 in patients with non-small cell lung cancer (NSCLC). A total of 236 patients were treated. One dose-limiting toxicity occurred at 6.4 mg/kg; therefore, 4.2, 4.5, and 4.8 mg/kg were selected for cohort expansion. Treatment-related adverse events (TRAEs; any/grade ≥ 3) occurred in 99.6%/57.2% of patients. Common grade ≥3 TRAEs included neutropenia (30.9%), leukopenia (25.0%), and thrombocytopenia (17.4%). Objective response rate was 34.7% in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) and platinum chemotherapy, 45.7% in EGFR-mutant NSCLC treated with EGFR TKIs, 20.0% in EGFR wild-type squamous NSCLC, and 35.7% in EGFR wild-type non-squamous NSCLC. Median progression-free survival and overall survival were 7.6 and 19.4 months, respectively, in EGFR-mutant NSCLC treated with EGFR TKIs and platinum chemotherapy. Overall, SYS6010 shows a manageable safety profile and encouraging antitumor activity in previously treated, advanced NSCLC.

Figure S7. The supplement to single-cell RNA-Seq and WB results of lung tissues 6 months after RT.

4118 Background: China bears a high biliary tract cancer (BTC) burden, with cholangiocarcinoma rising incidence ( > 6/100,000 vs 0.3–6/100,000 globally) and high mortality ( > 4/100,000). Over 60% of BTC patients are diagnosed at advanced stage (stage III/IV), and nearly two-thirds are unresectable. GEMOX regimen is a widely recognized standard of care in China, favored for its reduced renal toxicity and better tolerability compared with GemCis. Envafolimab is the world's first subcutaneously (SC) injectable anti-PD-L1 monoclonal antibody approved by China's NMPA. We report the final analysis of this pivotal trial, the first global phase III study initiated to evaluate immunotherapy plus chemotherapy in this setting. Methods: In this multicenter, open-label, phase III study in China, eligible patients (pts) with previously untreated, unresectable locally advanced/metastatic BTC were randomized 1:1 to envafolimab (2.5 mg/kg SC weekly) + GEMOX (gemcitabine 1000 mg/m² d1, 8; oxaliplatin 85 mg/m² d1, Q3W) or GEMOX chemotherapy alone. Chemotherapy was limited to 6 cycles in both arms. Stratification factors: primary site, disease stage, prior therapy, and ECOG PS. Primary endpoint: OS. Secondary endpoints: PFS, ORR (RECIST v1.1 by BICR), and safety. Results: 472 pts were randomized; 462 treated (envafolimab+GEMOX n = 232; GEMOX n = 230). At the final analysis, the primary endpoint was met well. Envafolimab+GEMOX significantly improved OS vs GEMOX (HR 0.723; 95% CI 0.585–0.880; P = 0.0016). Median OS was 10.9 months vs 8.6 months; 36-mo OS rates were 12.5% vs 7.7%. OS benefit was observed across subgroups, notably in intrahepatic cholangiocarcinoma (HR 0.705) and metastatic disease (HR 0.704). Median PFS (BICR) was 4.8 vs 4.6 months (HR 0.899; 95% CI 0.713–1.132); notably, the gallbladder cancer subgroup showed more favorable PFS benefit (HR 0.628). ORR was 27.6% vs 20.9%. Grade 3–4 TEAEs occurred in 69.4% (combination) vs 56.1% (chemo). irAEs occurred in 20.7%. Conclusions: This study demonstrates that adding subcutaneously administered envafolimab to GEMOX significantly improves OS with a manageable safety profile in advanced BTC. Compared with other regimens, the combination showed robust efficacy with a low rate of irAEs. Those findings establish envafolimab, the world's first SC PD-L1 inhibitor, combined with GEMOX as a new, effective, and convenient standard of care for this population. Clinical trial information: NCT03478488 .

Accumulating evidence supports the concept that DNA damage response targeted therapies can improve antitumor immune response by increasing the immunogenicity of tumor cells and improving the tumor immune microenvironment. Ataxia telangiectasia mutated (ATM) is a core component of the DNA repair system. Although the ATM gene has a significant mutation rate in many human cancers, including colorectal, prostate, lung, and breast, it remains understudied compared with other DDR-involved molecules such as PARP and ATR. Here, we found that either gene knockout or drug intervention, ATM inhibition activated the cGAS/STING pathway and augmented MHC class I in CRC cells, and these effects could be amplified by radiation. Furthermore, we found that MHC class I upregulation induced by ATM inhibition is dependent on the activation of the NFκB/IRF1/NLRC5 pathway and independent of STING. Animal experiments have shown increasing infiltration and cytotoxic function of T cells and better survival in ATM-deficient tumors. This work indicated that ATM nonsense mutation predicted the clinical benefits of radiotherapy combined with immune checkpoint blockade for patients with CRC. It also provides a molecular mechanism rationale for ATM-targeted agents for patients with CRC.

Figure S1. The supplement to tumor growth and percent survival curves.

In this phase 2 study (NCT05047991), patients with unresectable metastatic pancreatic adenocarcinoma were randomized to receive NALIRIFOX (liposomal irinotecan, 5-FU, leucovorin, and oxaliplatin) or gemcitabine plus nab-paclitaxel. The primary endpoint was progression free survival (PFS). Secondary endpoints included other efficacy outcomes (overall survival, objective response rate, disease control rate, and duration of response), as well as safety, pharmacokinetic parameters, and evaluation of the relationship between UGT1A1*6 and UGT1A1*28 polymorphisms and safety. A total of 117 patients were enrolled and randomly assigned to NALIRIFOX (n = 78) or gemcitabine plus nab-paclitaxel (n = 39). At a median follow-up of 18.7 months (interquartile range [IQR], 7.5–22.1) for NALIRIFOX and 12.1 months (IQR: 6.4–14.8) for the gemcitabine plus nab-paclitaxel, median PFS was 7.6 months (95

Colorectal cancer (CRC) represents a predominant global malignancy, characterized by increasing incidence and mortality rates. Recent investigations have underscored the gut microbiota as a pivotal element in the pathogenesis and progression of CRC. This review synthesizes current evidence regarding the association between gut microbial dysbiosis and CRC, with a particular emphasis on pathogenic bacteria such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, pks⁺ Escherichia coli, and Enterococcus faecalis, among others. The mechanisms through which these microbes contribute to tumorigenesis include the induction of DNA damage, the promotion of chronic inflammation, and the induction of immunosuppression, and the production of oncogenic metabolites. Additionally, the review examines the clinical implications of gut microbiota, highlighting their potential as non-invasive biomarkers for early CRC detection and their impact on the efficacy and toxicity of chemotherapy, radiotherapy, and immunotherapy. Furthermore, emerging microbiota-targeted interventions, such as fecal microbiota transplantation, dietary modification, and probiotics, are evaluated for their therapeutic potential. Despite substantial progress, challenges remain in standardizing microbial markers and optimizing individualized microbiota modulation strategies. Future studies integrating multi-omics and machine learning approaches may pave the way for microbiome-based precision medicine in CRC.