Abstract
Cancer immunotherapy represents a transformative strategy in modern oncology, utilizing the body’s immune system to recognize and eliminate malignant cells with precision. Unlike traditional therapies, which often directly target the tumor, immunotherapy enhances the immune system’s inherent ability to differentiate between healthy and cancerous cells, leading to more targeted and potentially longer-lasting therapeutic effects. The advent of immune checkpoint inhibitors (ICIs), particularly those targeting the PD-1/PD-L1 and CTLA-4 pathways, has marked a significant breakthrough in this field, yielding substantial clinical success in various cancer types. However, the therapeutic landscape is still challenged by issues such as the development of resistance mechanisms, heterogeneity in patient responses, and the limited efficacy of current ICIs across all tumor types.
Given these challenges, there is a critical need to identify and validate new immune targets that can synergize with existing therapies or function independently to overcome resistance and improve patient outcomes. This review provides a comprehensive overview of the latest research efforts focused on uncovering novel immune targets. By expanding the repertoire of immune targets, these discoveries aim to enhance the effectiveness of cancer immunotherapy, offering hope for more personalized and resilient treatment options. The integration of these novel targets into clinical practice could not only extend the benefits of immunotherapy to a broader spectrum of cancers but also mitigate some of the current limitations, paving the way for more durable and effective therapeutic strategies in the fight against cancer.
Keywords: Cancer immunotherapy; Immune Checkpoints; Co-Stimulatory Molecules; TAM Receptors; CD73, Adenosine pathway
Introduction: Cancer immunotherapy represents a groundbreaking strategy in contemporary oncology, utilizing the body’s immune system to target and eliminate malignant cells. Unlike traditional treatments that directly target tumors, immunotherapy aims to stimulate or enhance the immune system’s ability to recognize and eliminate cancer cells, offering the potential for more durable and targeted therapeutic outcomes [1]. Immunotherapy, including adoptive cell transfer (ACT) and immune checkpoint inhibitors (ICIs), is a cancer treatment that harnesses the power of the immune system to target and eliminate tumor cells. Used either on its own or alongside traditional treatments such as radiotherapy and chemotherapy, this approach has become a standard and highly successful option for treating many cancers [2,3].
Notably, immune checkpoint inhibitors (ICIs) that target PD-1/PD-L1 and CTLA-4 have gained prominence in clinical practice [2,3]. These therapies have achieved significant success by effectively releasing the brakes on the immune response, allowing the immune system to detect and attack tumors that previously evaded detection. Despite these advancements, challenges remain, such as the emergence of resistance mechanisms and the varying effectiveness of treatment across different types of cancer. This resistance, which can be primary (intrinsic) or acquired (secondary), is driven by complex cellular and molecular processes.
The TME is often immunosuppressive, containing regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) that inhibit T-cell activity. These cells secrete immunosuppressive cytokines, such as TGF-β and IL-10, which dampen the anti-tumor immune response. The abundance of these immunosuppressive cells and molecules can lead to primary resistance to ICIs by preventing effective T-cell infiltration and activation [2,3]. Tumor cells and immune cells in the TME can upregulate PD-L1 in response to interferon-gamma (IFN-γ) produced by activated T cells. This adaptive resistance mechanism creates a feedback loop where increased PD-L1 binding to PD-1 on T cells suppresses their activity. This adaptive response, particularly in tumors with high PD-L1 expression, is associated with resistance to PD-1/PD-L1 inhibitors [3,4]. Certain genetic alterations in tumors, such as mutations in JAK1/2 and loss of PTEN, have been associated with ICI resistance. JAK1/2 mutations can disrupt IFN-γ signaling, leading to impaired antigen presentation and immune evasion. Additionally, epigenetic changes, such as DNA methylation and histone modifications, can silence genes involved in antigen presentation and immune recognition, further contributing to immune evasion [2,3,4].
Consequently, there is a pressing need to identify novel immune targets that can complement existing therapies, broaden the spectrum of cancers that can be effectively treated, and improve overall treatment outcomes. This review critically examines the latest advancements in the field, focusing on the discovery and exploration of new immune targets for cancer immunotherapy.