Chinese Medical Journal article review synthesizes molecular mechanisms, current therapeutics, and emerging strategies in esophageal cancer

This authoritative review synthesizes 5 years of pivotal clinical and translational advances in esophageal cancer (EC), encompassing molecular pathogenesis, genomic and epigenetic landscapes, targeted therapeutic modalities and the tumor immune microenvironment. It underscores breakthroughs of immunotherapy in EC management while acknowledging slower progress in targeted treatments. Promising future directions include TKIs, CDK4/6 inhibitors, PI3K/AKT/mTOR pathway modulators, epigenetic regulators, ADCs, and rational combination strategies to overcome drug resistance and improve long-term patient survival outcomes.

Esophageal cancer (EC) is an aggressive and highly lethal malignancy with a rapidly growing global burden. It is histologically classified into two primary subtypes, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), which exhibit profound divergence in etiology, genomic profiles, and tumor microenvironment. Despite advancements in surgical resection, radiotherapy, and chemotherapy, long-term survival remains unsatisfactory due to late-stage diagnosis, high recurrence rates, intratumoral heterogeneity, and limited precision medicine options. To address this critical gap, Professor Feng Wang from the Sun Yat-Sen University Cancer Center, China, and a team of researchers have published a comprehensive review in the Chinese Medical Journal. This work systematically summarizes breakthroughs in EC clinical trials, molecular mechanisms, targeted therapies, and immunotherapies over the past 5 years. The findings were published online on July 08, 2026.

This review commences by addressing the epidemiological challenges and early detection of EC. ESCC exhibits high prevalence in East Asia, particularly China, whereas EAC incidence is rising in Western countries. Traditional endoscopic screening is constrained by invasiveness and cost; however, innovative technologies, including liquid biopsy based on cell-free DNA methylation profiling and artificial intelligence (AI)-assisted endoscopy, have markedly improved early detection accuracy and patient compliance. These noninvasive methods enable large-scale screening and timely intervention, with the potential to significantly reduce global EC-related mortality.

At the molecular level, the review provides an in-depth analysis of the distinct genomic and epigenetic landscapes of ESCC and EAC. ESCC is characterized by frequent TP53 mutations, alongside frequent alterations in NOTCH1, NFE2L2, and cell-cycle regulatory genes. In contrast, EAC is associated with high chromosomal instability, frequent HER2 amplification, and inactivation of tumor suppressor genes such as TP53 and SMAD4. Epigenetic aberrations, including DNA methylation, histone modifications, and dysregulated noncoding RNAs, further drive tumor progression and represent promising reversible therapeutic targets. These molecular disparities lead to divergent treatment responses, emphasizing the necessity for subtype-specific precision strategies.

The review then evaluates the progress and limitations of targeted therapies, which have advanced more slowly compared to immunotherapy. Trastuzumab remains the standard first-line treatment for HER2-positive EAC, while ramucirumab is approved for second-line therapy. Investigations into key signaling pathways, including EGFR, VEGF/VEGFR, FGFR, PI3K/AKT/mTOR, CDK4/6, and WEE1, have yielded limited clinical benefits, often hampered by tumor heterogeneity, pathway redundancy, and rapid acquisition of drug resistance. Encouragingly, emerging platforms such as ADCs and bispecific antibodies have shown promising efficacy by delivering highly selective cytotoxicity and enhancing anti-tumor immune activity.

Immunotherapy has revolutionized EC management over the past decade. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1, in combination with chemotherapy, have become the standard first-line treatment, significantly improving overall survival for both ESCC and EAC patients. However, a substantial proportion of patients exhibit primary or acquired resistance to ICIs. The EC tumor immune microenvironment is highly immunosuppressive, characterized by enrichment of regulatory T cells, tumor-associated macrophages, myeloid-derived suppressor cells, and cancer-associated fibroblasts. Hypoxia and metabolic reprogramming further impair T-cell function and facilitate immune escape.

To overcome these barriers, the review highlights a spectrum of innovative strategies: rational combinations of ICIs with targeted therapy or radiotherapy, adoptive cell therapies such as CAR-T and TCR-T cells, therapeutic cancer vaccines, oncolytic viruses, and gut microbiota modulation. These approaches aim to reprogram the tumor microenvironment, turning "cold” immunosuppressive tumors into “hot” inflamed lesions amenable to immunotherapy.

“Despite remarkable therapeutic advances, EC remains a highly lethal disease, underscoring the urgent need to identify novel therapeutic vulnerabilities and explore innovative combination regimens,” the authors emphasize. They note that future clinical practice will rely on multiomics integration, reliable predictive biomarkers, and liquid biopsy for real-time disease monitoring to achieve truly personalized treatment.

In conclusion, this comprehensive review delivers a clear, up-to-date framework for clinicians, researchers, and drug developers to accelerate translational progress in EC. With ongoing innovation in targeted agents, rational immunotherapy combinations, and early detection technologies, the prognosis for patients with EC is expected to improve significantly in the near future.

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Reference

Title of original paper: Molecular Mechanisms, Current Therapeutics, and Emerging Strategies in Esophageal Cancer: A Comprehensive Review

Journal: Chinese Medical Journal

DOI: 10.1097/CM9.0000000000004194

About Prof. Feng Wang from Sun Yat-Sen University Cancer Center, China
Dr. Feng Wang is currently a Professor, Assistant President and Director in the Department of Medical Oncology at Sun Yat-Sen University Cancer Center, Guangzhou, China. Awarded The National Science Fund for Distinguished Young Scholars, she holds many academic posts, including the National high-level talents, Vice Chairman of Youth Council of China Anti-Cancer Association. She has extensive experience and expertise in the field of precision treatment and immunotherapy for digestive tract tumors. Dr. Wang sees thousands of patients with gastrointestinal cancers annually and has initiated or participated in many investigators initiated and NMPA approved clinical trials. Dr. Wang has published over 65 articles as corresponding/co-corresponding or first author in leading journals, including Nature Medicine, Cancer Cell, Journal of Clinical Oncology, JAMA Oncology, Annals of Oncology, and The Lancet Gastroenterology and Hepatology. Ten studies have been written into 14 authoritative guides at home and abroad, such as NCCN, ASCO, CSCO, CACA, etc.

Funding information
This work was supported by the National Natural Science Foundation of China (No. 82425048), the New Cornerstone Science Foundation through the XPLORER PRIZE, the Young Talents Program of Sun Yat-sen University Cancer Center (No. YTP-SYSUCC-0018), and the Natural Science Foundation of Gansu Province (No. 25JRRA767).