Background
Digestive system cancers are a leading cause of cancer-related morbidity and mortality worldwide, accounting for 35% of cancer deaths annually. These cancer entities are highly heterogeneous and complex in their etiology, molecular characteristics, and therapeutic management. Over the past decade, genomic and functional studies have provided unprecedented insights into the biology of digestive tract cancers, identifying genetic drivers of tumor progression and key interaction points between tumor cells and the immune system. This knowledge is continuously being translated into new therapeutic concepts and targets, dynamically reshaping the treatment landscape for these tumors.
On January 15, 2025, Matthias P. Ebert of Heidelberg University published a review in Signal transduction and targeted therapy titled "Digestive cancers: mechanisms, therapeutics and management". In this review, the etiology and molecular pathology of the six most common digestive cancers, including esophageal cancer, gastric cancer, biliary tract cancer, pancreatic cancer, hepatocellular carcinoma, and colorectal cancer, are outlined. A comprehensive description of the current stage-dependent drug treatments for these malignancies is provided, including chemotherapy, targeted therapy, and immunotherapy. For each cancer entity, an overview of recent therapeutic advances and research progress is provided. Finally, it describes how new insights into tumor heterogeneity and immune escape have deepened the understanding of treatment resistance and provides an outlook on innovative treatment strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates, and targeted therapy.
Esophageal squamous cell carcinoma
The influencing factors of esophageal squamous cell carcinoma (ESCC) are smoking and drinking, and it is also related to genetic factors. In ESCC, there are changes in receptor tyrosine kinases and downstream signaling mediators, dysregulation of the TGF-β pathway and changes in chromatin remodeling, and changes in other signaling pathways. Early and locally advanced, resectable ESCC is usually treated with surgical resection and chemoradiotherapy. The treatment of advanced unresectable or metastatic ESCC is limited to chemotherapy with poor prognosis. Recently, immune checkpoint inhibitors have been discovered that can block the cancer cell-mediated immune evasion can downregulate and promote antitumor immune responses. Immune checkpoint inhibitors have demonstrated survival benefits in ESCC, significantly changing current therapeutic approaches. While inhibitors are generally better tolerated than traditional chemotherapy, they still exhibit their own toxicity profiles and the development of drug resistance.
Adenocarcinoma of the gastric and esophageal junction
Gastric cancer (GC) is usually caused by environmental factors, including infectious and non-infectious factors such as Helicobacter pylori infection. The Cancer Genome Atlas Research Network has proposed a classification of GC into four molecular subgroups: MSI, EBV, GS , and CIN.
First-line and second-line treatment for metastatic GC and GEJ adenocarcinoma is based on a combination of chemotherapy and antibody therapy. The choice of treatment regimen depends largely on the patient's performance status, previous treatment, and the expression of predictive biomarkers, including HER2, MSI, PD-L1, and more recently, CLDN18.2. Combining chemotherapy with immune checkpoint inhibitors has been shown to improve patient survival and response rates. With the emergence of new targets such as CLDN18.1 and FGFR2b, as well as improved HER2- and immune checkpoint-targeted antibodies, the main challenge will be to optimize the molecular stratification of GC and identify synergistic combinations of targeted agents.
Biliary tract cancer
Biliary tract cancer, or cholangiocellular carcinoma (CCA), comprises a heterogeneous group of malignancies. CCA carcinogenesis is a complex process involving genomic and epigenetic alterations that modulate processes such as DNA repair, receptor tyrosine kinase signaling, and epigenetic regulation. Despite recent advances in diagnostic approaches and treatment, CCA has an overall poor prognosis. Combination chemotherapy with immunotherapy has become the standard of care for first-line treatment of CCA. Combinations of immunotherapy or immunotherapy with other agents have not met with significant success to date. A better understanding of the mechanisms underlying carcinogenesis and cancer progression is necessary to expand the patient population that can benefit from tailored therapeutic approaches.
Hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is a primary liver cancer. The most important risk factor is chronic viral hepatitis infection, particularly HBV and HCV, which lead to chronic inflammation and liver cell damage, promoting genetic mutations and abnormal cell growth. HBV and HCV infection induce this inflammation through viral replication, immune cell activation, and the production of proinflammatory cytokines. These signaling pathways activate key tumor drivers, such as TGF-β, Wnt/β-catenin, Notch, EGF, HGF, VEGF, SHH, and YAP/TAZ, ultimately enhancing cell survival, proliferation, and evasion of apoptosis.
Early-stage HCC is typically treated with surgical resection, while intermediate-stage HCC is often treated with TACE, which involves injecting chemotherapy into the hepatic artery supplying the tumor, followed by embolization to induce ischemic tumor necrosis. Systemic targeted therapy has revolutionized the treatment of advanced HCC, with immune checkpoint inhibitors opening a new chapter in systemic HCC treatment and improving overall survival. Another combination of immune checkpoint inhibitors and TKIs has not demonstrated a survival benefit.
Pancreatic cancer
Pancreatic cancer is the fifth leading cause of cancer-related death worldwide, with pancreatic ductal adenocarcinoma (PDAC) being the most common type. KRAS mutation is the most common genetic alteration in pancreatic cancer, present in over 90% of patients. KRAS activation promotes cell cycle progression and survival through the RAF/MEK/ERK and PI3K/AKT signaling pathways.
For metastatic PDAC, systemic therapy is indicated for the relief of tumor-related symptoms and the prolongation of survival. The EGFR inhibitor erlotinib combined with gemcitabine was also approved for the first-line treatment of PDAC after demonstrating a survival benefit compared to gemcitabine monotherapy. With the subsequent approval of more effective combination therapies, this regimen plays only a minor role in current clinical practice, and FOLFIRINOX will likely continue to be used most frequently as first-line therapy for patients with a good performance status.
Specific inhibitors targeting the KRAS G12C mutation, such as sotorasib and adagrasib, have shown some efficacy in early clinical trials but are currently only effective in a small number of patients. The rational design of effective combination therapies remains challenging and requires extensive clinical testing.
Colorectal cancer
Colorectal cancer (CRC) is the third most common cancer worldwide. Patients in the early or locally advanced stages are usually treated with surgical resection. For stage III patients, adjuvant chemotherapy is usually required after surgery.
Immune checkpoint inhibitors have significantly improved cancer treatment. In CRC, they are the standard of care for metastatic or unresectable disease with MSI/dMMR disease. The therapeutic landscape for CRC is continually evolving, driven by extensive clinical and translational research efforts. Therefore, we anticipate numerous new developments in the coming years, particularly in the areas of precision medicine, immunotherapy, and microbiome research.
Treatment of gastrointestinal cancers-current challenges
Tumor heterogeneity and plasticity: Tumor heterogeneity and plasticity make the response of gastrointestinal cancer to treatment complex. Its heterogeneity can occur at multiple levels such as genetics, epigenetics and environment, affecting the treatment effect. Plasticity allows cancer cells to adapt to environmental perturbations without changing the genetic background, such as anti-tumor treatment, making treatment more difficult.
Immune evasion in gastrointestinal cancers: Tumor-intrinsic mechanisms include genetic alterations that lead to the activation of oncogenic signaling pathways that induce immune evasion, such as activation of the Wnt signaling pathway, which leads to T cell rejection. Tumor-extrinsic mechanisms that lead to immune escape primarily include autologous and paracrine signals, such as growth factors and chemical factors that influence innate and adaptive immune responses. For example, in the tumor microenvironment of CRC liver metastases, high TGF-β levels can produce an immunosuppressive state, while blocking TGF-β can increase the tumor's sensitivity to immune checkpoint blockade .
on the stage of the tumor , different immuno-oncology treatment strategies may be required.
Converting cancer genomic data into actionable targets: Converting cancer genomic data into actionable targets faces challenges, and the widespread implementation of precision oncology in the management of gastrointestinal cancers requires multifaceted efforts, including more equitable access to genetic services and infrastructure and resources for analyzing and interpreting genomic data.
Treatment of gastrointestinal cancer-future directions
Future treatments for gastrointestinal cancer will focus on deepening and expanding precision medicine and immunotherapy, including the development of novel inhibitors targeting key gene mutations such as KRAS, optimization of CAR-T cell therapy, and innovative strategies targeting the tumor microenvironment. Furthermore, research will focus on exploring immune escape mechanisms, developing combination therapy options to overcome drug resistance, and further analyzing tumor biological characteristics through multi-omics technologies to achieve more personalized and effective treatment strategies.
Summarize
Digestive system cancers represent a significant burden of disease. With the advent of genotype-specific KRAS inhibitors and pan-KRAS inhibitors, more patients with digestive system cancers are expected to benefit from targeted therapies. This precision oncology approach will be complemented by novel antibodies, such as bispecific antibodies and antibody-drug conjugates targeting tumors with abundant expression of specific cell surface proteins, such as CLD18.2. Further molecular characterization of digestive system cancers will yield additional cell surface targets in the future, expanding the therapeutic spectrum of antibodies. With advances in various drug treatment areas, determining the optimal combination of immunotherapy, targeted therapy, and chemotherapy, and discovering biomarkers that predict the efficacy of these combinations, will be a major challenge. Finally, advances in other areas of cancer management, such as radiotherapy and surgery, will also reshape the treatment of digestive system cancers. Taken together, these advances will lead to more complex and multidisciplinary management of digestive system cancers, resulting in better oncological outcomes in the future.
