Cancer remains one of the leading causes of death worldwide [1], despite advancements in diagnostics and treatment. Traditional therapies, such as surgery, radiotherapy (techniques such as 3D conformal stereotactic (body) radiotherapy (SBRT), intensity-modulated radiation therapy (IMRT), and enhanced imaging systems such as image-guided radiation therapy (IGRT)) [2], [3], and chemotherapy, such as alkylating agents, antimetabolites, and topoisomerase inhibitors, often are burdened with numerous side effects and the development of resistance [4], [5], [6], [7], [8], [9], [10]. Consequently, there is a growing interest in exploring new therapeutic strategies that could enhance treatment efficacy and reduce the risk of resistance.

Since neurons can directly communicate with tumor cells through the so-called neuro‑neoplastic synapses, while indirect regulation occurs via the autonomic and sensory nervous systems [11], [12], [13], the interest in exploring neurobiological pathways as therapeutic targets in oncology has risen. One promising avenue is modulation of the dopaminergic system, which plays a significant role in various biological processes, including tumor development [14], [15], [16], [17].

Dopamine (DA), a catecholamine neurotransmitter, exerts its effects through five types of receptors (DRD1–DRD5), which are grouped into two main subfamilies: D1-like receptors (DRD1 as well as DRD5) and D2-like receptors (DRD2, DRD3, and DRD4) [18], [19], [20]. They are expressed not only in the central nervous system (CNS) [21] but also in other tissues, including cancer cells [22], [23].

The role of DA in cancer is multifaceted, through affecting processes such as cell proliferation, apoptosis, angiogenesis, and metastasis [24], [25], [26], [27]. For instance, activation of DRD1 has been shown to inhibit tumor growth in certain cancer types [28], [29], [30]. DRD2 agonism has also been reported to exert inhibitory effects. In fact, DRD2 knockout animals implanted with melanoma cells exhibit enhanced tumor growth and metastatic spread [31]. Moreover, certain DRD2 agonists, such as bromocriptine, can suppress proliferation in MCF-7 breast cancer cells [32] and HCC-LM3 hepatocellular carcinoma cells [33], [34]. However, the effects of dopamine signaling in cancer are highly context-dependent and vary across different tumor types and microenvironments, since in some cases DRD2 activation can support aggressive cancer cell traits, including spheroid formation [35].

In view of the complexity of DA's role played in cancer, there still exists a growing awareness of therapeutic strategies that could precisely modulate dopaminergic signaling to achieve desired anticancer effects. A promising direction is the development of hybrid compounds—molecules engineered to simultaneously target multiple pathways implicated in disease mechanisms, particularly those driving tumor progression. These hybrid agents aim to combine the benefits of dopaminergic modulation with other therapeutic mechanisms, such as kinase inhibition or immune modulation, within a single molecular entity. This strategy seeks to enhance therapeutic efficacy, reduce the risk of resistance, and minimize adverse effects associated with conventional treatments.

In this review, we will explore the current understanding of DA receptor signaling in cancer and discuss the potential of hybrid compounds as a novel therapeutic strategy. By integrating insights from both dopaminergic signaling and multi-target drug design, we wish to provide a comprehensive overview of how hybrid molecules could be leveraged to improve cancer treatment outcomes.