Cancer is a complex and heterogeneous disease that poses a significant challenge to modern medicine. Despite significant advances in cancer therapy, conventional treatments such as chemotherapy, radiotherapy, and surgery have limitations, including poor efficacy and systemic toxicity. Therefore, there is an urgent need for novel and effective therapies that can selectively target cancer cells while sparing normal cells. Recent advances in the field of immune therapy and virotherapy have led to the development of promising new approaches that harness the power of nature to improve cancer therapy (Kontermann et al., 2021). 

Among these approaches, Antibody-Drug Conjugates (ADCs) and Oncolytic viruses have emerged as promising candidates for targeted cancer therapy. ADCs are a class of targeted cancer therapies that use monoclonal antibodies to selectively deliver cytotoxic drugs to cancer cells, while Oncolytic viruses are viruses that are genetically engineered to selectively infect and kill cancer cells (Tsuchikama et al., 2018). These novel therapies offer several advantages, including improved efficacy, reduced toxicity, and increased specificity compared to conventional cancer treatments. In this review, we will discuss the latest developments in the field of ADCs and Oncolytic viruses, their mechanisms of action, clinical efficacy, and challenges facing their clinical translation. The goal of this review is to provide a comprehensive overview of the current state of these promising natural-based cancer therapies and their potential for revolutionizing cancer treatment (Uddin et al., 2022; Fu et al., 2022).

Essential element of adcs

Leucine metabolism plays a critical role in Acute Myeloid Leukemia (AML) progression, and leucine deprivation can inhibit leukemic cell growth, induce cell cycle arrest, and enhance differentiation. Additionally, combining leucine deprivation with chemotherapy shows synergistic potential, making it a promising therapeutic strategy, though the precise molecular mechanisms, including its effects on the mTOR pathway, need further investigation (Hasan et al., 2024). Antibody-drug conjugates, or ADCs, are a novel type of targeted cancer therapeutics with the promise to increase therapy efficacy while lowering toxicity. ADCs enable the targeted delivery of extremely effective cytotoxic drugs (Fig. 1) directly to cancer cells by combining the cytotoxic potential of chemotherapeutic agents with the specificity of monoclonal antibodies (Fu et al., 2022). Monoclonal antibodies are proteins that can specifically recognize and bind to certain molecules, known as antigens, that are found on the surface of cancer cells (Fig. 1). By attaching to these antigens, the antibodies can deliver the cytotoxic drug to the cancer cells while sparing healthy cells (Zahavi et al., 2020).

The cytotoxic drugs used in ADCs are potent chemotherapeutic agents that can kill cancer cells by disrupting their DNA or inhibiting their cell division. The drug is attached to the monoclonal antibody through a linker molecule (Fig. 1) that can release the drug only when the antibody binds to the cancer cell (Ponziani et al., 2020). The design of the linker molecule is critical for the effectiveness of the ADC, as it must be stable in circulation and release the cytotoxic drug only within the cancer cell to minimize toxicity to healthy cells (Sheyi et al., 2022). ADCs have shown promising results in preclinical and clinical trials for various types of cancer, including breast cancer, lung cancer, and lymphoma. By selectively targeting cancer cells (Fig. 1), ADCs can reduce the side effects associated with traditional chemotherapy drugs, which can harm healthy cells and cause severe toxicity (Dean et al., 2021). However, the development of ADCs also poses several challenges, such as the optimization of the design of the monoclonal antibody, linker molecule, and cytotoxic drug, as well as the efficient delivery of the ADC to the cancer cells (Dean et al., 2021).

Fig. 1: The components and functions of an ADCs drug, which typically consists of a target antigen, an antibody, a linker, and a cytotoxic drug (Fu et al., 2022).

Structure of ADCs 

An ADCs is composed of three components: a monoclonal antibody (mAb), a linker, and a cytotoxic drug. Monoclonal Antibody (mAb): The mAb is designed to target a specific antigen expressed on the surface of cancer cells (Fig. 2). It is derived from a single clone of immune cells that produce antibodies against the target antigen. The mAb is engineered to have high specificity and affinity for the target antigen to ensure that the ADC selectively binds to cancer cells and avoids binding to healthy cells (Zahavi et al., 2020). 

Fig. 2: ADCs action mechanism is depicted graphically. ADC is made up of three structural sections: antibody, payload, and linker. The antigen on the cell surface distinguishes the monoclonal antibody, and ADC enters the target cell via endocytosis. Cellular proteases cleave the linker, releasing cytotoxic medicines that precisely destroy the target cancer cells (Tsuchikama et al., 2018).

Linker: The linker is a chemical bridge that connects the mAb and the cytotoxic drug. It plays a crucial role in controlling the release of the drug from the ADC and determining its pharmacokinetics and pharmacodynamics. The linker should be stable in circulation but able to release the cytotoxic drug upon internalization of the ADC into the target cell. There are two types of linkers, cleavable and non-cleavable, depending on whether the linker is designed to break down inside the target cell or not (Sheyi et al., 2022). Cytotoxic Drug: The cytotoxic drug is a highly potent and toxic molecule that can kill cancer cells. The choice of drug depends on the type of cancer being targeted and the desired mechanism of action. Examples of cytotoxic drugs used in ADCs include microtubule inhibitors, DNA-damaging agents, and RNA synthesis inhibitors (Ponziani et al., 2020).

Mechanism of action of ADCs

The mechanism of action of ADCs involves several steps:

Selective binding: The mAb component of the ADC selectively binds to the target antigen expressed on the surface of cancer cells (Fig. 2). This binding specificity ensures that the ADC is delivered to cancer cells, sparing healthy cells from the cytotoxic effects of the drug (Esapa et al., 2023).

Internalization: The ADC is internalized into the cancer cell through receptor-mediated endocytosis. Release of cytotoxic drug: The linker connecting the mAb and cytotoxic drug is cleaved in the intracellular environment, releasing the cytotoxic drug (Fig. 3) (Shi et al., 2022).

Targeted killing

The released cytotoxic drug exerts its toxic effects on the cancer cell, leading to cell death (Fig. 2). The mechanism of action of the cytotoxic drug depends on the type of drug used. For example, microtubule inhibitors disrupt the microtubule network, leading to mitotic arrest and cell death, while DNA-damaging agents cause DNA strand breaks, leading to apoptosis (Fu et al., 2022). Immune response: In some cases, the ADC can also induce an immune response against the cancer cells, further enhancing the anti-tumor activity of the therapy. The immune response can be triggered by several mechanisms, such as antibody-dependent cell mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and activation of the immune system through the release of tumor antigens (Zahavi et al., 2020).

Key component of oncolytic viruses

Oncolytic viruses (OVs) are a class of viruses that can selectively infect and kill cancer cells while sparing normal cells. This unique property of OVs makes them an attractive candidate for cancer therapy. One of the key components of OVs is their ability to selectively target cancer cells. This is achieved through several mechanisms, including the overexpression of certain receptors on the surface of cancer cells that are not present on normal cells. OVs can be engineered to recognize and bind to these receptors, which initiates the viral replication cycle and ultimately leads to the destruction of cancer cells (Jhawar et al., 2017). Another key component of OVs is their ability to induce an immune response. OVs can trigger the release of cytokines and chemokines, which recruit immune cells to the site of infection (Fig. 3). These immune cells can then recognize and kill cancer cells that have been infected by the OVs. In addition, OVs can also enhance the presentation of tumor antigens to the immune system, which can further stimulate an anti-tumor immune response (De Matos et al., 2020). One example of an OVs that has shown promising results in clinical trials is talimogene laherparepvec (T-VEC), a modified herpes simplex virus that has been approved by the US FDA for the treatment of melanoma. T-VEC has been shown to selectively replicate in and lyse cancer cells, as well as induce an anti-tumor immune response. In clinical trials, T-VEC has demonstrated an overall response rate of 33% and a complete response rate of 11% in patients with advanced melanoma (Conry et al., 2018).

Genetically engineered oncolytic viruses 

Genetically engineered oncolytic viruses are a promising class of viruses that are being developed for cancer therapy. These viruses are genetically modified to selectively target and kill cancer cells while sparing healthy cells in the body. The development of these viruses involves a few steps, including selecting a virus that can infect and replicate within cancer cells, and then genetically modifying the virus to enhance its specificity for cancer cells and reduce its ability to infect healthy cells (Zhang et al., 2021). One approach to modifying these viruses is to introduce therapeutic genes that can selectively kill cancer cells or stimulate the immune system to attack cancer cells. For example, some genetically engineered oncolytic viruses have been designed to express a cytokine or chemokine that attracts immune cells to the site of the tumor (Fig. 3), while others express a prodrug-converting enzyme that converts a non-toxic prodrug into a toxic drug specifically within cancer cells (Fukuhara et al., 2016).

The development of ADCs and oncolytic viruses has revolutionized cancer therapy, offering a targeted approach to killing cancer cells while minimizing damage to healthy cells. Preclinical and clinical studies have shown promising results, with some patients experiencing complete remission (Coats et al., 2019). However, there are limitations to these therapies, including tumor heterogeneity, off-target effects, and the potential for resistance. These limitations can impact the effectiveness of the therapy and overcoming them remains a challenge for the field. Furthermore, the use of these therapies in combination with other treatments such as chemotherapy, radiation therapy, and immunotherapy may offer even greater efficacy in fighting cancer (Mokhtari et al., 2017). Overall, ADCs and oncolytic viruses represent an important advance in cancer therapy and highlight the potential for innovative targeted therapies to improve patient outcomes.

Dr. Lynne Lawrance and Dr. David Qualtrough deserve grateful acknowledgement for their insightful discussions and organization of research on matters related to current issues. Additionally, the support and discussion of crucial issues in the article by Dr. Lili Ordonez are greatly appreciated. Their provision of multifarious topics significantly boosted my skills. Partial support for this work was provided by the University of the West of England.

There is no conflict of interest in this review paper.