According to the World Health Organization, cancer is a large group of diseases that can manifest in any tissue or organ of the body when some aberrant cells multiply uncontrollably, move past their usual boundaries, and spread to the neighboring organs or tissues of the body. The latter phenomenon is termed metastasis and is the prime reason for mortality associated with cancer [1].

In the global cancer report 2020, approximately 10 million deaths are associated with cancer, wherein lung cancer (18 %) is leading the charts, followed by colorectal (9.4 %), liver (8.3 %), stomach (7.7 %), and breast (6.9 %) cancer. Out of approximately 20 million new cancer cases, breast cancer (11.7 %) is leading in incidence rate, followed by lung (11.4 %), colorectal (10 %), and prostate (7.3 %) cancer [2]. Solid cancers are highly frequent in prevalence, in which there is an estimation of about 80 % of all cancer types derived from some solid cancer organs, and the share of cancer-related death from solid cancers is more than 85 % [3]. Present-day treatment options for cancer are chemotherapy, surgery, and radiotherapy, but all these treatments have their own adverse reactions, such as damage to normal tissue along with cancer tissue. Weinberg and Hanahan have delineated six hallmarks of cancer that may aid in differentiating tumor and normal tissue characteristics and suggest better treatment options. The six hallmarks are as follows: enabling replicative immortality, evading growth suppressors, activating invasion and metastasis, sustaining proliferative signaling, resisting cell death, and inducing angiogenesis [4]. The application of these hallmarks to characterize cancer and to find new treatment options are being investigated. In addition, cancer variants with a high proliferation fraction respond well to chemotherapy and are curable. But the cure rate with chemotherapy is significantly less, and the relapse rate is high with cancer variants of a low fraction of proliferation. Further, the effective cancer treatment dose of chemotherapeutic agents has also been associated with immunosuppressive activity [5]. The other challenging aspects related to cancer therapeutics are targeting of neoplasm, resistance qualities (making them resistant to anticancer medications), cancer diagnosis-related problems, lack of reliable biomarkers, poor cancer epigenetic profiling, and specificity of existing epi-drugs, limitations with conventional chemotherapeutic agents and the last but not the least metastasis [6].

Current cancer treatment modalities can be bifurcated broadly into conventional and novel/modern therapy [7]. The unique characteristics, for example, the type of cancer, its grade, and the site of localization, directs the road to shortlist the treatment modalities and their progress. The most prominently utilized conventional treatments are surgery, radiotherapy, and chemotherapy, whereas new treatment modalities involve immunotherapy, hormone therapy, anti-angiogenic therapy, dendritic cell-based immunotherapy, and stem cell therapy [8]. Chemotherapy works by preventing malignant cells from dividing, but it also affects fast-proliferating normal cells including bone marrow, gastrointestinal tract cells, and hair follicles, resulting in adverse effects.[9], [10], [11] The molecules employed in chemotherapy exhibit diverse mechanisms of action, aiming to disrupt various stages of the cell cycle and prevent uncontrolled proliferation. One such class of molecules is antimetabolites, which mimic essential cellular components, such as nucleotides, interfering with DNA synthesis. They trick cancer cells into using the drug instead of the molecules they need to make DNA. When cancer cells use antimetabolites in their DNA, the drugs interfere with their ability to replicate properly and the cancer cells die. Some examples of antimetabolites include: 5-fluorouracil (5-FU), Capecitabine, Floxuridine, Cytarabine, Gemcitabine, Decitabine, Vidaza [12]. Another group of chemotherapy agents includes alkylating agents, which induce DNA damage by forming covalent bonds with DNA strands. Cyclophosphamide is a widely employed alkylating agent that cross-links DNA strands, impeding cell replication and triggering apoptosis [13]. Platinum-containing compounds, like cisplatin, are metal-based chemotherapy agents that form DNA adducts, causing structural distortions and preventing normal DNA function. These molecules are particularly effective against testicular and ovarian cancers [14].

Radiotherapy, also known as radiation therapy, is a crucial component in the treatment of various cancers, utilizing high doses of radiation to target and destroy cancer cells. This therapeutic approach aims to disrupt the ability of cancer cells to divide and grow, ultimately leading to their death. The success of radiotherapy relies on the interaction between ionizing radiation and biological molecules within the targeted cells [15], [16]. One key molecular player in radiotherapy is DNA, the genetic material responsible for cell function and replication. Ionizing radiation, such as X-rays or gamma rays, induces double-strand breaks in the DNA helix, initiating a cascade of cellular responses. These breaks can lead to cell cycle arrest and apoptosis, preventing the uncontrolled proliferation of cancer cells [17]. Moreover, free radicals generated during radiation exposure contribute to DNA damage. Radiolysis of water produces reactive oxygen species (ROS), causing oxidative stress in cells. The resulting damage to lipids, proteins, and DNA amplifies the therapeutic effects of radiotherapy [18].

Surgery stands as a cornerstone in the comprehensive approach to cancer treatment, often serving as the primary method for removing tumors and preventing their spread. Surgical interventions in cancer treatment are designed to excise cancerous tissue, either entirely or as much as possible, and may involve the removal of nearby lymph nodes to assess potential metastasis. One critical aspect of cancer surgery is the determination of the tumor's stage, which guides treatment decisions. Staging involves assessing the extent of tumor invasion, the involvement of nearby structures, and whether the cancer has spread to other parts of the body. Precise staging informs surgeons about the optimal strategy for tumor removal and helps oncologists tailor postoperative therapies. Minimally invasive techniques, such as laparoscopy and robotic-assisted surgery, have revolutionized cancer surgery, offering patients less invasive options with reduced recovery times. These methods utilize small incisions and advanced technologies, providing surgeons with enhanced visualization and precision during procedures. In certain cases, surgeons may perform palliative surgery to alleviate symptoms and improve the quality of life for cancer patients. This type of surgery aims to manage complications related to the tumor, such as obstruction or bleeding, without necessarily aiming for a complete cure [19].

Targeted therapy has emerged as a revolutionary approach in the realm of cancer treatment, offering a more precise and tailored strategy to combat malignancies. Unlike traditional chemotherapy, which indiscriminately targets rapidly dividing cells, targeted therapy specifically focuses on the molecular and genetic aberrations unique to cancer cells, sparing normal, healthy tissues. This precision enhances therapeutic efficacy while minimizing adverse effects [20]. One hallmark of targeted therapy is the identification and targeting of specific molecules involved in cancer growth and survival. Receptor tyrosine kinases (RTKs), for instance, are frequently overexpressed or mutated in various cancers, driving uncontrolled cell proliferation. Drugs like imatinib, a tyrosine kinase inhibitor, selectively block the activity of these receptors, disrupting the signaling pathways that promote cancer cell growth. This targeted approach has demonstrated significant success in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors [21]. Another notable targeted therapy strategy involves the use of monoclonal antibodies. These antibodies are designed to recognize and bind to specific proteins on the surface of cancer cells, triggering immune responses that lead to cell death. Trastuzumab, an antibody targeting the HER2 receptor, has proven effective in treating HER2-positive breast cancer by inhibiting the signaling pathways that fuel tumor growth [22]. Moreover, small molecule inhibitors, such as vemurafenib for BRAF-mutated melanoma, illustrate the success of targeting specific genetic mutations driving cancer progression. By interfering with the abnormal signaling cascades initiated by these mutations, targeted therapy disrupts the cancer cells' ability to survive and proliferate [23]. [24], [25], [26].

Cancer immunotherapy has emerged as a groundbreaking approach in the field of cancer treatment, harnessing the power of the immune system to target and eliminate cancer cells. This innovative strategy represents a paradigm shift from traditional cancer treatments, such as chemotherapy and radiation, by utilizing the body's natural defense mechanisms to combat the disease. One of the key principles underlying cancer immunotherapy is the enhancement of the immune system's ability to recognize and attack cancer cells. Tumor cells often develop mechanisms to evade detection by the immune system, allowing them to proliferate unchecked. Immunotherapy works by activating or enhancing immune responses, enabling the immune system to recognize and destroy cancer cells more effectively. A notable example of cancer immunotherapy is immune checkpoint blockade, which involves targeting proteins that act as checkpoints to regulate immune responses. Drugs like pembrolizumab and nivolumab inhibit these checkpoint proteins, such as PD-1 or PD-L1, preventing them from suppressing immune activity. This unleashes the immune system to mount a robust attack against cancer cells. Another promising avenue in cancer immunotherapy is adoptive cell therapy, where immune cells, such as T cells, are isolated from the patient, genetically modified or activated ex vivo, and then reintroduced into the patient's body. Chimeric Antigen Receptor (CAR) T-cell therapy is a notable example, where T cells are engineered to express specific receptors targeting cancer cells, resulting in a highly targeted and potent anti-cancer response [27], [28]. Combining different checkpoint inhibitors or combining checkpoint inhibitors with other treatments is yet another innovation of immunotherapy and it has shown significant increase in efficacy in treating various cancers [29]. Cancer vaccine is yet another innovation in the field of immunotherapy having an implication in decreasing the probability of an individual developing cancer [30].

The immune system has built-in checkpoints, such as programmed cell death protein 1 (PD-1) and its ligand PD-L1, that play a crucial role in regulating immune responses. Cancer cells often exploit these checkpoints to evade detection by the immune system. Immune checkpoint blockers (ICBs) are a class of drugs designed to block these inhibitory signals, thereby unleashing the immune system to recognize and attack cancer cells. One of the pioneering drugs in this field is pembrolizumab, which targets PD-1, and nivolumab, which also targets PD-1, and atezolizumab, which targets PD-L1. These drugs have shown remarkable success in treating various cancers, including melanoma, lung cancer, and renal cell carcinoma [31]. PD-1 is a receptor protein that is expressed on the surface of activated T cells, B cells, and other immune cells whereas PD-L1 is a protein that is expressed on the surface of various cells, including cancer cells, as well as immune cells and some normal tissues. PD-1 becomes activated when it binds to its ligands, primarily PD-L1 and PD-L2. This interaction occurs in the peripheral tissues and lymphoid organs. When PD-1 binds to PD-L1 or PD-L2, it delivers an inhibitory signal to the T cell. This inhibitory signal dampens the activity of the T cell, preventing it from mounting an overly aggressive immune response. Cancer cells often exploit the PD-1/PD-L1 pathway to evade detection and destruction by the immune system. By expressing PD-L1, cancer cells can suppress the immune response, allowing them to proliferate and avoid elimination. Immune checkpoint inhibitors, such as anti-PD-1 or anti-PD-L1 antibodies, block the interaction between PD-1 and PD-L1. This blockade releases the brakes on the immune system, allowing it to recognize and attack cancer cells more effectively [32]. Besides PD-1 and its ligands PD-L1/L2, numerous other immune checkpoints also hold crucial roles in regulating the immune system and have emerged as potential targets for therapeutic intervention. One such checkpoint is cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), also recognized as CD152, expressed on activated T cells. It competes with CD28 for binding to the costimulatory molecules CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells (APCs). Engagement of CTLA-4 leads to the suppression of T cell activation, thereby dampening the immune response. The blockade of CTLA-4 using monoclonal antibodies like Ipilimumab has successfully triggered anti-tumor immune responses and is an approved therapy for melanoma [33]. Another immune checkpoint is lymphocyte-activation gene 3 (LAG-3 or CD223), primarily expressed in activated T cells, regulatory T cells, and natural killer (NK) cells. LAG-3 interacts with major histocompatibility complex class II molecules, suppressing T cell proliferation and cytokine production when engaged [34]. T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is another immune checkpoint molecule with emerging therapeutic potential. TIM-3 is expressed on various immune cells, including T cells, natural killer cells (NK), and dendritic cells. It interacts with galectin-9 and phosphatidylserine, inducing T cell exhaustion and immune tolerance [35].

The recently discovered immune checkpoint molecule, v-domain Ig suppressor of T cell activation (VISTA), is expressed in myeloid cells, T cells, and dendritic cells. It plays a role in inhibiting T cell activation. Research into VISTA is in its early stages, but preclinical studies indicate its potential as an immunotherapeutic target. Another immune receptor within the CD28 family is T cell immunoreceptor with Ig and ITIM domains (TIGIT), which is present in some NK and T cells. TIGIT is overexpressed on tumor antigen-specific (TA-specific) CD8 + T cells and CD8 + tumor-infiltrating lymphocytes (TILs) in melanoma patients. Blocking TIGIT has been linked to increased cell proliferation, cytokine production, TIL CD8 + T cell activity, and TA-specific CD8 + T cell degranulation. A phase I clinical trial is currently recruiting to assess the efficacy and safety of two drugs, IBI939 (NCT04150965) and COM902 (NCT04354246), but no results have been reported yet [32].

Stem cells are used in cancer therapy for immuno-reconstitution, tissue regeneration, and as vehicles for the delivery of chemotherapy. In addition, stem cells also exhibit distinct biological behaviors such as self-renewal, differentiation, and production of immune cells. Because of its improved target on tumors and decreased off-target events, it could increase the efficacy of other therapies. Renewal of the hematological system damaged by tumor cells and by chemotherapy is achieved by stem cells. Adult stem cells are preferred over other types as they do not have ethical issues and are readily available and accessible [36]. Personalized medicines have also emerged as no single therapeutic agent works similarly on patients with the same diagnosis. It involves understanding the molecular mechanisms and identifying appropriate biomarkers for individualized treatment. To aid in the selection of the most effective therapy for cancer patients, validated biomarkers with adequate specificity and sensitivity are required [37], [38].

As our understanding of the intricate landscape of cancer therapies evolves, it becomes imperative to explore innovative approaches that address the challenges posed by traditional treatments. One promising avenue is the PD-1/PD-L1 immune checkpoint pathway, a key player in the regulation of immune responses and a focal point for groundbreaking advancements in cancer immunotherapy. By delving into this pathway, we aim to harness its potential to enhance treatment outcomes and pave the way for more effective and targeted interventions against various malignancies.