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.