Cancer remains a major global health problem, with an estimated 19.3 million new cases and ~10 million deaths reported worldwide in 2020 alone (1). The 2024 report of the American Cancer Society projected that 2,001,140 new cancer cases would be diagnosed in the United States in 2024, with an estimated 611,720 deaths (2). Globally, cancer has become the second leading cause of death in the past 100 years (3). Stomach, colorectal, esophageal, pancreatic, ovarian, cervical, kidney, breast, lung, prostate, thyroid and other cancers threaten human health in several ways (4–14). Early detection and timely intervention are crucial for patient prognosis, and early diagnosis and treatment have always been the guiding principles in managing such diseases (15). The detection rate of tumors has increased with the advancements in diagnostic techniques. However, most tumors are detected at an advanced stage, resulting in most patients missing the opportunity for surgical resection treatment. Therefore, determining the target for tumor biotherapy is an essential step in cancer treatment (16,17).

Biomarkers are molecules in the blood, other body fluids or tissues that serve as markers of normal or abnormal processes, conditions or diseases, and can be used to monitor how the body responds to therapy for a certain disease or condition (16). Biomarkers can enable precise and individualized treatment for patients with tumors, thereby opening novel avenues for treating highly heterogeneous neoplastic lesions (18). Classical tumor markers, such as carcinoembryonic antigen, cancer antigen 125 and cancer antigen 19-9, have been widely used in clinical practice and can serve as indicators of biological processes, states or conditions to determine the occurrence, development and prognosis of cancer. However, these markers may also be expressed in nontumor tissues under the influence of certain factors (19). Therefore, the identification of sensitive and specific tumor biomarkers is critical for cancer treatment.

Discoidin protein domain receptor (DDR) tyrosine kinases belong to the tyrosine kinase receptor family, which is subdivided into 20 subfamilies based on the homology of ligand-binding extracellular domain features. Abnormalities in these tyrosine kinases are associated with several diseases, including cancer, chronic inflammation and fibrosis (20,21). DDR1 is predominantly expressed in epithelial cells of different tissues, whereas DDR2 is expressed in fibroblasts, myofibroblasts, smooth muscle cells, chondrocytes and other mesenchymal cells (22). In addition, their interaction with MAPK, PI3K, JAK/STAT and Rho-GTPases can induce signal transduction to activate ERK1/2, Akt, cytokine and RhoA-signaling pathways. The DDR2 receptor serves a role in cytoskeletal dynamics, cell proliferation, differentiation, cell survival, adhesion, migration, metabolism, cytokine signaling and immune response (23). In a previous study, the expression of DDR2 on tumor-associated fibroblasts increased the hardness of tumor tissues (24).

The present review summarizes the latest research progress on DDR2, its role in cancer and its underlying mechanisms of action, including its abnormal expression in cancer and its prognostic value. Additionally, the current status of global drug and future design prospects for DDR2 are also reviewed.

The molecular structure of DDR includes an extracellular binding domain, a transmembrane domain and an intracellular kinase domain. The extracellular binding domain is composed of a discoidin (DS) domain and a DS-like domain for collagen binding (25). The DDR2 gene is located on human chromosome 1 (1q23.3) and consists of 19 exons, of which exons 4-19 are transcribed into a mRNA transcript that is then translated to produce the DDR2 protein product. Connective tissue cells originating from the embryonic mesoderm can be stimulated and activated by collagen types I, II, III and X, and they participate in several physiological and pathological processes. The extracellular binding region of DDR2 consists of N-terminal DS domains that can bind to collagen, DS-like domains and extracellular phagocyte membrane regions, providing N- and O-glycosylation sites and MMP cleavage sites. N- and O-glycosylation sites are important sites for the glycosylation of DDR2. The glycosylation modification of DDR2 can enhance its signal-conduction ability (26). The MMP cleavage sites of DDR2 are associated with the mutual regulation between DDR2 and MMPs (27). MMPs can cleave several substrates, including cell surface receptors. Therefore, the presence of MMP cleavage sites in DDR2 can lead to the cleavage and inactivation of DDR2 by MMPs, thereby regulating the activity of DDR2 (28). DDR2 can act in conjunction with myosin IIA to regulate the adhesion and traction of collagen and condense collagen fibrils into a denser arrangement, thereby reshaping the generation and arrangement of collagen fibers (29).

For further analysis, the present study mapped the DDR2 in tissues, cells and organs using the Human Protein Atlas (HPA) database (www.proteinatlas.org), which integrates proteomics, transcriptomics and systems biology data. The results revealed that DDR2 was most abundant in nontumor cells in the single-celled expression cluster (https://www.proteinatlas.org/ENSG00000162733-DDR2/cell+line). Furthermore, the RNA expression levels of DDR2 in several tissues were summarized using the HPA database (https://www.proteinatlas.org/ENSG00000162733-DDR2/tissue).

DDR2 is abnormally expressed in numerous human solid tumors and has been associated with tumorigenesis. The current research results of DDR2 in several solid tumors are summarized in Table I.

Furthermore, analysis of data from the Tumor Immune Estimation Resource database (http://cistrome.org/TIMER/) revealed that the DDR2 expression was different across breast duct carcinoma with subsequent lung adenocarcinoma, breast cancer, colon adenocarcinoma, kidney chromophobe, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, prostate adenocarcinoma, rectal adenocarcinoma, skin cutaneous melanoma, thyroid carcinoma, uterine corpus endometrial carcinoma and other cancers (Fig. 1). In addition, a literature search revealed the involvement of DDR2 in ovarian, breast, lung, colorectal and other cancers through several pathways (30–33). Several functions of DDR2 in solid tumors are presented in Fig. 2.

The TME refers to the noncancerous cells and their components present in the tumor environment, including fibroblasts, endothelial cells, neurons, fat cells, adaptive cells and innate immune cells. This term also refers to the continuous interaction between tumor cells and the TME, which serves a decisive role in the cancer development, progression and metastasis, as well as in the therapeutic response of the tumor (93,94). The ECM is an important component of the TME. Tumor cells interact with the ECM to promote cancer cell proliferation, migration, invasion, angiogenesis and immune escape; thus, the ECM has become a key target in cancer treatment (95,96). The ECM is mainly composed of proteoglycans, glycoproteins, matrix proteins, osteopontin, thrombo-reactive protein and structural proteins, which undergo dynamic remodeling to maintain the TME (97,98). DDR2 is uniquely positioned to act as an ECM sensor and can be activated by ECM collagen-induced binding protein receptors. Processes such as migration, proliferation and cytokine secretion are regulated, leading to ECM remodeling and reconstruction in an unbalanced homeostasis (24,99). DDR2-expressing CAFs can promote metastasis of ovarian cancer by influencing ECM remodeling (100).

The population of fibroblasts found in both primary and metastatic cancers is collectively referred to as CAFs. They are the most abundant cell types in the TME and are the central hub of cross-communication among several cells in the tumor stroma (101,102). Aside from being highly heterogeneous, CAFs are differentially expressed in different tumor tissues, and several CAF subtypes have been identified in numerous cancers. Targeted CAF therapy is currently a research hotspot in antitumor therapy. In CAFs, DDR2 expression is directly associated with their ability to reshape the ECM (103,104). For example, a previous study reported that DDR2-expressing CAFs regulate periostin (POSTN) protein via integrin subunit B1 (ITGB1), promoting ovarian cancer metastasis. DDR2 and POSTN signal through the PI3K/AKT and Src pathways and can serve as potential therapeutic targets for ovarian cancer (105). In a breast cancer study, DDR expression by CAFs increased the aggressiveness of breast tumor cells through regulation of the basement membrane and paracrine signaling. Based on these findings, the study indicated that the independent tyrosine kinase activity of DDR2 in breast tumor cells and breast tumor CAFs regulates breast cancer metastasis. Therefore, adjuvant therapy targeting tyrosine kinase activity should not only target tumor cells and stromal cells but also target the tumor stromal cells. Furthermore, drugs that inhibit tyrosine kinase-dependent and tyrosine kinase-independent effects are urgently needed (106).

To date, immune checkpoint-targeted drugs, such as anti-cytotoxic T lymphocyte-associated protein 4, anti-PD-1 and anti-PD-L1, as well as other new targeted drugs, have achieved notable results in several cancer immunotherapies. However, accumulating evidence suggests that positive response rates remain low in patients receiving immune checkpoint-targeted drugs and drug resistance emerges, which is an issue that warrants attention (107,108). DDR1 and DDR2 have been identified as potential therapeutic targets for MAPK inhibitor resistance, and mutations in DDR2 have shown particular efficacy with dasatinib in squamous cell lung carcinoma (109,110). The tumor immune microenvironment is composed of tumor cells, immune cells and cytokines. These components can be classified as antitumor and protumor, and the interaction between them determines the trend of antitumor immunity (111). These reported findings demonstrate that DDR2 is involved in multiple mechanisms mediating the interactions between tumor cells and immune cells, and thus immunotherapy targeting DDR2 may provide new perspectives to tumor therapy.

EMT refers to the cellular process through which epithelial cells lose their properties and gain interstitial properties to facilitate cell movement. This process is abnormally activated in human cancers and contributes to enhanced tumor initiation, cell migration, invasion, metastasis and therapeutic resistance (112). DDR2 is expressed in interstitial cells and can be activated by collagen, thus we hypothesize that DDR2 is associated with organ fibrosis and EMT. DDR2 can promote tumor metastasis and invasion through EMT in ovarian cancer, breast cancer, stomach cancer, colorectal cancer, thyroid cancer and other cancers (37,38,43,53,58,80). Therefore, as DDR2 can promote tumor metastasis and invasion, therapies targeting the tumor microenvironment in patients with cancer with high DDR2 expression may be effective.

Due to its potential use in antitumor therapy, several drugs targeting DDR2 have been developed and used in clinical trials and research. The present review used the Pharnexcloud Cloud database (https://www.pharnexcloud.com/) to retrieve information on DDR2 global clinical trials (Table II) and drug development (Table III) (113–118). In addition, the prognostic value of DDR2 in solid tumors was also summarized in Table IV.

Table V provides a comparison between the present review and the study by Trono et al (119). Moreover, the present review included multiple studies on DDR2 with the aim of including more innovations. The strengths of the present review are as follows: i) The review systematically outlines the role of DDR2 in several solid tumors, such as ovarian cancer, breast cancer, gastric cancer and liver cancer (a total of 12 categories). The expression, function and clinical significance of DDR2 in each cancer type are listed in Table I; ii) the present review describes the single-cell expression profile of DDR2 in nontumor cells based on the HPA database, emphasizing its specific distribution in stromal cells and providing a cell-type basis for targeted therapy; iii) the present review describes the current status of clinical trials, drug and antibody research, and development of anti-DDR2 drugs using databases such as Pharnexcloud; iv) the present review offers the following mechanistic innovations: It proposes a new mechanism by which the DDR2-Hippo pathway regulates ferroptosis, and also explains that, although high expression of DDR2 promotes breast cancer recurrence, it also enhances the sensitivity of tumor cells to ferroptosis, thus providing a new idea for combined targeted therapy. Moreover, it identifies a new axis of immune resistance in liver cancer, observing that the DDR2/STAT3/PD-L1 positive feedback loop mediates oxaliplatin resistance. It also describes that the recruitment of MDSC by CCL20 creates an immunosuppressive microenvironment that promotes immune escape; v) the present review identifies a new target of stromal cell, revealing that in CAFs DDR2 regulates POSTN through ITGB1 to promote ovarian cancer metastasis, and also highlights the therapeutic value of targeting the DDR2-POSTN-PI3K/Akt axis; and vi) the present review focuses on clinical transformation and unsolved issues by associating DDR2 with chemotherapy resistance (such as cisplatin resistance in ovarian cancer and sorafenib resistance in liver cancer), proposing new pathways (such as DDR2/NF-κB/c-Rel signaling) and guiding the design of combination therapy; and proposing the combination of DDR2 inhibitors and PD-1/PD-L1 antibodies to reverse ‘cold tumors’ (such as breast cancer) and exploring its potential to affect T-cell infiltration by regulating collagen arrangement. In summary, the primary strength of the present review lies in its integration of multi-cancer clinical data, systematic analysis of drug resistance mechanisms and comprehensive review of current therapeutic developments targeting DDR2. It addresses the gaps in cancer-type coverage in other reviews and aligns more closely with the practical needs of clinicians and researchers in translational medicine. Although available studies on DDR2 emphasize mechanistic explorations, the present review broadens the scope by incorporating clinical data and cross-cancer analyses, thereby expanding potential applications. The information provided in the present review offers notable practical value for clinical decision-making. Furthermore, the review complements other investigations in the field and contributes to advancing DDR2 research in both basic science and clinical settings.

Several studies have reported that DDR2 serves different pivotal roles in numerous types of solid tumor, especially through ECM and CAFs. It also participates in multiple mechanisms to promote tumor metastasis and drug resistance. Both ECM and CAFs, as well as EMT, are a major focus of tumor research. As the research on DDR2 progresses, biological processes involved in tumor occurrence and development are likely to be revealed. In addition, as the potential of DDR2 inhibitors continues to be investigated through drug development and clinical trials, new perspectives are likely to emerge in the treatment of tumors.

The present article offers a comprehensive and insightful review of DDR2 as a promising target in solid tumors. It examines key aspects, including the structure and function of DDR2, its expression in several tissues and tumors, and its role in the tumorigenesis of different types of cancer, such as ovarian, breast and stomach cancers. This broad coverage is useful for researchers looking for a comprehensive resource for DDR2 in solid tumors. Additionally, it bridges the gap between basic research and clinical application by assessing the current global progress on DDR2 drugs and antibodies, which is crucial for translating laboratory findings into potential cancer treatments. Finally, the present review provides potential new directions for the pursuit of effective cancer treatments through DDR2-targeted strategies.