Xiaotian Zhang

China’s oncology drug development ecosystem has shifted from rapid pipeline expansion toward clinical value–driven innovation. We review regulatory reform and the 2015 to 2025 evolution of clinical development across small molecules, mAbs, multispecific antibodies, antibody–drug conjugates, and cell and gene therapies. China’s disease burden and enrollment capacity have enabled globally relevant advances in EGFR-mutant lung cancer, gastrointestinal malignancies, hepatocellular carcinoma, nasopharyngeal carcinoma, and CLDN18.2-directed therapies. We highlight persistent challenges in target and modality convergence, biomarker definition, therapeutic window optimization, manufacturing consistency, and globally interpretable evidence generation and discuss how artificial intelligence may connect target discovery, drug design, and clinical trial optimization more efficiently. Significance: China has become a major source of oncology trials and modality innovation, but scale alone will not ensure global impact. This review links regulatory reform, disease-specific opportunity, target biology, therapeutic format, and evidence quality across a decade of solid tumor development. It defines the conditions under which China-originated programs can generate globally practice-changing evidence. See related article by Shi, p. XX .

Claudin 18.2 (CLDN18.2)-targeted CAR-T cell and antibody therapies show promise against gastrointestinal cancers, but biomarkers predictive of long-term benefit and therapeutic sensitization strategies are needed. Here we show that proteins carried by circulating extracellular vesicles (EVs) can reflect and influence the efficacy of CLDN18.2-targeted therapies. By profiling serial plasma samples of patients from the CT041-CG4006 trial (CLDN18.2- CAR-T-therapy) or the GLOW trial (Zolbetuximab), we identified EV-associated CLDN18.2, PD1 and PD-L2 as therapeutic markers and integrated them into a signature (CPP-score) for better predictive robustness. Mechanistically, specific EV-proteins exhaust CAR-T cells, neutralize CLDN18.2-targeted-antibodies, activate immunosuppressive IL-6-expressing cancer-associated fibroblasts, and alter the TH1/TH2 balance, thereby reshaping the tumor microenvironment and interfere with CLDN18.2-targeted therapies. Strategies including combining anti-PD1 antibody or CAF inhibitor, CLDN18.2-CAR-T plus CLDN18.2-antibody, and depleting plasma EVs, can sensitize CLDN18.2-CAR-T/antibody by countermeasuring EV-proteins’ therapeutic interferences. Collectively, our work provides potential options to monitor and improve CLDN18.2-targeted therapies in clinical practice.

Immune checkpoint blockade has achieved remarkable success in cancer treatment; however, enhancing its efficacy remains a challenge. Here we identified an immunoregulatory micropeptide encoded by the long noncoding RNA USP30-AS1 gene, highly expressed in tumor-associated macrophages. The so-designated UEIS (USP30-AS1-encoded immune suppressor) drives macrophages toward a protumorigenic phenotype, thereby inhibiting antitumor T cell immunity. Mechanistically, UEIS is induced in macrophages by cGAS–STING–type I interferon signaling at a relatively late stage following tumoral DNA stimulation, and exerts a negative feedback regulation on the type I interferon signaling by forming biomolecular condensates with TBK1, thereby inhibiting its interaction with STING. Both an intrinsically disordered region and an alpha helix at the extreme N terminus of UEIS were essential for its function. A peptide designed to disrupt UEIS–TBK1 condensation successfully inhibited UEIS function in tumor-associated macrophages, leading to reduced tumor growth and increased response to immune checkpoint blockade. Thus, these findings highlight UEIS as a promising therapeutic target for cancer treatment.

FGFR2 has garnered attention as a promising therapeutic target for gastric cancer (GC) because of its role in GC progression. Infigratinib, an FGFR1-3 selective tyrosine kinase inhibitor, has shown potential in preclinical GC models. Infigratinib was evaluated in a phase 2 trial for patients with FGFR2-amplified GC or gastroesophageal junction (GEJ) adenocarcinoma who had failed two or more lines of systemic treatment for locally advanced or metastatic disease. A total of 21 patients received 125 mg of infigratinib orally once daily on a "3 weeks on, 1 week off" schedule. Infigratinib showed preliminary antitumor activity in this molecularly selected population, as reflected by a confirmed objective response rate of 23.8% (95% CI, 8.2-47.2) with median progression-free survival of 3.4 months and median overall survival of 6.7 months. The most common grade 3-4 adverse events were elevated aspartate aminotransferase, decreased white blood cell count, and neutropenia. No treatment-related deaths occurred. Exploratory genomic analyses identified alterations in individual patients with disease progression that may be associated with resistance; however, these findings were based on a limited number of cases and should be interpreted as hypothesis-generating. The findings support continued investigation of FGFR-targeted strategies in FGFR2-amplified GC/GEJ adenocarcinoma, while underscoring the need for larger studies, refined biomarker selection, and deeper characterization of resistance mechanisms. NCT05019794, Registered 28 July 2021, https://clinicaltrials.gov/study/NCT05019794 .

Supplementary Figure 1 Specificity profiling of the anti-B7-H3 scFv using the Membrane Proteome Array (MPA). Supplementary Figure 2 Study Dose-Escalation Schema. Supplementary Figure 3 Association of Peak CAR-T Cell Expansion (Cmax) with Clinical Outcomes. Supplementary Figure 4 Lymphocyte Reconstitution Dynamics Following UTAA06 Infusion. Supplementary Figure 5 Longitudinal Serum Cytokine Dynamics Following UTAA06 Infusion. Supplementary Figure 6 Association of Cytokine Fold-Change with Clinical Outcomes. Supplementary Figure 7 Host CD8+ Activation and CAR-T Copy Number Kinetics for Individual Patients. Supplementary Figure 8 Longitudinal analysis of NK cell activation and inhibitory markers in patient P10.

Supplementary Table 1 Final Product Release Criteria for UTAA06 Supplementary Table 2 Representativeness of Study Participants Supplementary Table 3 Baseline Characteristics and Clinical Outcomes of Individual Patients Supplementary Table 4 Characteristics of UTAA06 Products Supplementary Table 5 Serum Tumor Marker Kinetics

Purpose:The aim of the study was to evaluate the safety, pharmacokinetics, and preliminary clinical activity of UTAA06, an “off-the-shelf” allogeneic B7-H3–targeted chimeric antigen receptor (CAR) Vδ1T-cell therapy, in patients with pretreated, advanced B7-H3–positive solid tumors.Patients and Methods:In this first-in-human, phase I, dose-escalation study (NCT06372236), 10 patients with advanced solid tumors (including gastric, colorectal, hepatocellular, ovarian, and neuroendocrine cancers) were enrolled. Following lymphodepletion chemotherapy (cyclophosphamide and fludarabine), patients received UTAA06 infusion across three dose levels (5 × 108, 8 × 108, or 1 × 109 cells). The primary endpoint was safety. Secondary endpoints included pharmacokinetics and antitumor efficacy.Results:UTAA06 demonstrated a manageable safety profile; no GVHD was observed, and cytokine release syndrome was limited to two transient grade 1 events. A single dose-limiting toxicity (grade 3 pneumonitis) was reported in one patient at the 5 × 108 cell dose level. Although UTAA06 demonstrated signals of biological activity, including transient reductions in serum tumor markers in 50% of patients, no objective response by RECIST v1.1 criteria was observed. Further analysis identified that the limited CAR T-cell persistence was likely driven by subclinical host-versus-graft rejection.Conclusions:This study provides clinical proof of concept for allogeneic B7-H3–targeted CAR-Vδ1T cells as a safe platform with low risk of GVHD and demonstrable biological activity in solid tumors. However, clinical efficacy was constrained by limited cellular persistence caused by host immune rejection. Future strategies are required to enhance the durability and therapeutic potential of this allogeneic approach.

PURPOSE: The clinical efficacies of third- or later-line therapies for metastatic colorectal cancer (CRC) are extremely limited. The purpose of this study was to evaluate the safety and efficacy of a chimeric antigen receptor T (CAR T) cell targeting guanylyl cyclase 2C (GUCY2C) that was steadily expressed in all stages of CRC in a phase I study. PATIENTS AND METHODS: This was an open-label, single-center, phase I study, consisting of a 3 + 3 pattern dose-escalation phase and a dose-expansion investigation. Tumor tissues were histologically confirmed positive for GUCY2C expression. Four dose levels were tested in the dose-escalation phase, including 3 × 10 ⁸ (DL1), 6 × 10 ⁸ (DL2), 12 × 10 ⁸ (DL3), and 20 × 10 ⁸ (DL4) CAR T cells. The primary end points were safety and tolerability within 28 days after the first infusion. RESULTS: In dose-escalation phase, dose-limiting toxicity was not observed. DL3 was chosen for dose-expansion study. A total of 20 patients with metastatic CRC were infused with GUCY2C CAR T after lymphodepletion, and only one patient (5.0%) showed grade 3 cytokine release syndrome and neurotoxicity. Grade 3 diarrhea occurred in 11 patients (55.0%). Of 19 evaluable patients, the objective response rate (ORR) was 26.3%, with all responding patients in DL3 and DL4 groups. Of 10 patients in the DL3 group, the ORR was 40.0% and the median progression-free survival time (mPFS) was 7.0 months. Among patients showing medium-to-high GUCY2C expression in the DL3 group, the ORR achieved 50.0% and the mPFS was 9.0 months. CONCLUSION: GUCY2C CAR T showed acceptable safety profile and high response rate in patients with third- or later-line CRC, and the clinical efficacy was associated with CAR T dose level.

This study aimed to assess real-world treatment patterns, human epidermal growth factor receptor 2 (HER2) testing, and clinical outcomes in patients with HER2-positive locally advanced unresectable or metastatic gastric or gastroesophageal junction cancer (GC/GEJC) in China. A multicenter retrospective study (REHEARSAL Study; NCT06585501) was conducted across nine hospitals in China. Patients with HER2-positive, locally advanced unresectable or metastatic GC/GEJC who initiated first-line therapy were included. Treatment patterns in the first, second, and third lines, HER2 testing practice, and real-world clinical outcomes were assessed. In total, 805 patients were included (median age of 62.00 years; 77.14% male and 22.86% female). From 2018 to 2023, the first-line treatment pattern showed an increase in the use of anti-HER2 therapies-from 60.83 to 90.19%. There was a notable increased application of HER2 monoclonal antibody (mAb) with immunotherapy (from 0.83 to 60.78%) in the first line. In the second line, 12.28% of patients were administered vascular endothelial growth factor receptor inhibitor in 2023. HER2-antibody-drug conjugate monotherapy and combination therapy had become the predominant third-line treatment (50.00%) in 2023. Tissue biopsy was the primary sample type for HER2 testing (99.25%). Re-biopsy was performed in 6.96% of cases. Anti-HER2 therapies exhibited benefits with a median real-world progression-free survival of 8.94, 5.52, and 4.96 months in the first-, second-, and third-line settings, respectively. In China, HER2 mAb with or without immunotherapy remained the main first-line option for HER2-positive locally advanced unresectable or metastatic GC/GEJC, with a rising trend toward combination with immunotherapy. The second-line outcomes highlight the urgent need for effective treatment options, underscoring the importance of further real-world studies to better define their role. ClinicalTrials.gov identifier, NCT06585501.