The development of cancer may require mutations in multiple genes. Mutations may affect different aspects of cellular growth control. Such as cell cycle control/regulatory genes (oncogenes and tumor suppressor genes), DNA repair genes, angiogenesis genes, telomere regulation, cell morphology/metastasis, and immune surveillance [5,16,17]. Basically, genes that regulate all these properties, directly and/or indirectly, can contribute to cancer. In addition to alterations in cancer-related genes, telomerase activation is necessary for the sustained growth and development of most cancer types, except those that use alternative pathways for telomeric integrity and repair. Telomeres are the ends of chromosomes, specialized nucleoprotein structures that maintain chromosome stability and, thus, the genome [18,19]. When telomeres shorten to a critical level, the cell declines further cellular division. Telomeres normally shorten with each cell division and when damaged. Cancer cells maintain telomere length and stability mainly by reactivating telomerase, unlike normal cells [18,20].

Targeted cancer therapies primarily target a specific mutation or molecular pathway that drives tumor progression. While conventional therapies affect both cancerous and normally dividing cells, therefore all cells that have division potential, targeted therapies only aim to suppress division in cancer cells by limiting the effects of molecules involved in tumor growth, progression, and metastasis. Moreover, targeted therapies generally have fewer side effects for patients because healthy cells are less affected than with conventional cancer treatments.

There are several mechanisms in cancer cells that can be targeted for therapies. One key mechanism of targeted cancer therapies is the inhibition of cancer cell growth by either blocking protein expression or normalizing their activity. For example, the human epidermal growth factor receptor 2 (HER2) receptor is overexpressed in some breast cancers, leading to aggressive tumor growth. Trastuzumab (Herceptin) is a monoclonal antibody that specifically binds to the HER2 protein, inhibiting its function and preventing further tumor proliferation [38]. Lapatinib, a dual EGFR/HER2 inhibitor, is particularly useful in cases resistant to monoclonal antibody therapy like Trastuzumab [39].

Targeted therapies provide personalized treatments to cancer patients. Some of the U.S. Food and Drug Administration (FDA)-approved targeted therapy drugs are listed in Table 1. Tyrosine kinase inhibitors (TKIs) have proved to be one of the main treatment options. Normally, tyrosine kinases phosphorylate the tyrosine residues on proteins for the regulation of cell cycle progression and signal transduction. The mechanistic action of TKIs is to inhibit the activity of an enzyme involved in tumor growth, neoplastic transformation, cellular survival, and migration. TKIs achieve this by competitively binding to the ATP-binding sites of kinases so that the kinase becomes inactive. TKIs can be both single-kinase-specific or target multiple kinases—the development of next-generation TKIs aimed to overcome resistance mutations and improve selectivity [40].

A prominent example is the use of Imatinib (Gleevec), a tyrosine kinase inhibitor often used in targeted cancer therapies, to treat chronic myelogenous leukemia (CML). It targets the BCR-ABL fusion protein, which is formed by a gross chromosomal rearrangement that results in the Philadelphia chromosome, a driver of growth in CML cells. CML can be transformed into a manageable chronic condition with this treatment [41]. Imatinib is also effective in GIST patients with mutations in the KIT or PDGFRA tyrosine kinases, significantly improving survival rates [42]. However, over long-term use, imatinib can be ineffective due to drug resistance. To overcome this problem, second-generation TKIs have been developed. These include Dasatinib and Nilotinib [43].

Additionally, any genetic mutation present in cancer cells can, in principle, serve as a target for cancer therapies, because if the mutation can be targeted, only the cells that harbor it would be subject to the administered drug. In many non-small cell lung cancers (NSCLC), mutations in the epidermal growth factor receptor (EGFR) result in overexpression, increased activity, or increased ligand affinity. Drugs like Erlotinib (Tarceva) and Gefitinib (Iressa) work by inhibiting EGFR signaling downstream of secondary messengers, thereby blocking signal transduction pathways, reducing tumor size, and improving survival outcomes in patients with EGFR mutations [44]. In addition, Osimertinib is particularly effective against T790M resistance mutations. It has become the first-line therapy for EGFR-mutant NSCLC [45].

Moreover, some types of renal cell carcinomas (RCC) can also be targeted by TKIs. RCC is mainly driven by angiogenesis due to mutations in VEGFR. TKIs such as Sunitinib, Sorafenib, and Axitinib inhibit VEGFR and have improved outcomes in RCC patients [46]. Multi-targeted TKIs, including Lenvatinib and Sorafenib, have shown improvements in patients with advanced thyroid cancers, particularly those who do not respond to radioactive iodine therapy [47].

Although there is mounting evidence on the potential of targeted therapies, there are limitations that cannot be ignored. Because cancer cells have a higher mutation rate, alternative signaling pathways can be activated, promoting progression or relapse. In addition, some cancers cannot be targeted because the target mutations are not present. Currently, the potential for targeted therapy can only be increased through new target discoveries, combination therapies, and the development of novel therapies.

Tumor immunology and immunotherapy are among the rapidly evolving fields, significantly contributing to higher treatment success when applied alongside surgery and/or other treatment modalities, including chemotherapy and radiotherapy. Over the past five decades, advancements driven by molecular biology technologies have made cancer immunotherapy emerge as one of the most promising and fast-growing fields [48,49]. Cancer immunotherapy harnesses the power of the immune system as a transformative approach, redirecting its components to attack and eradicate tumor cells [50]. Unlike other therapeutic strategies, immunotherapy works by stimulating or enhancing the immune system, the body’s defense system [49]. Although several immunotherapeutic approaches have been developed and shown to improve treatment outcomes, it is important to note that, not all patients benefit from these strategies, as individual’s tumors are highly heterogeneous [51]. This represents a major challenge for scientists in the field, who are striving to understand the mechanisms underlying resistance to immunotherapies [52]. In this section, current tumor immunotherapy strategies will be explored including immune checkpoint inhibitors (ICIs), adoptive cell therapy, cancer vaccines and a more recent approach, immune cell engagers.

Stem cells are characterized as undifferentiated cells that self-renew and can differentiate into more specialized cells throughout the body. Stem cell research gained more focus and impact with the identification of cells with extensive proliferative potential in acute myeloid leukemia (AML) in 1997 by Bonnet and Dick [111]. These isolated cells were further characterized as cancer stem cells (CSCs) with the CD34⁺CD38^- phenotype. This study widely acknowledged the existence of leukemia stem cells, which then led to the development of the theory of “CSCs” in 2001 [112]. The concept of CSCs has since expanded to encompass the identification of various solid tumors. A few years later, Al-Hajj et al. isolated CD44⁺CD24^-/low CSCs from breast tumors in 2003 [113]. This study showed that 200 CSC cells could form tumors in recipient mice within 12 weeks, whereas 10,000 non-special breast cancer cells could not. Late in the same year, CD133⁺ CSC population from diverse brain tumors was purified by Sheila K Singh et al. [114]. These studies suggesting potential CSCs across both hematologic and solid malignancies have substantiated the CSC theory; more research is focused on further understanding the role of stem cells in cancer, as well as on using and targeting stem cells in cancer.

Currently, mesenchymal stem cells (MSCs) are actively being investigated for their potential to regenerate diseased or damaged tissues [115]. These cells are currently utilized in clinical trials and are primarily derived from bone marrow (BM), adipose tissue, and connective tissues. Additionally, hematopoietic stem cells (HSCs) and neural stem cells (NSCs) are significant adult stem cell populations commonly used in cancer therapies [116,117,118]. HSCs, found in the bone marrow, can generate all mature blood cell types. Notably, the only HSC-based therapy approved by the FDA involves the infusion of HSCs derived from umbilical cord blood for the treatment of hematopoietic system disorders, including hematologic malignancies and inherited blood disorders [119]. Omisirge (omidubicel-onlv) is a nicotinamide-modified, cord blood-derived hematopoietic stem cell transplant therapy. It was approved by the FDA in 2023 for patients with hematologic malignancies [120]. More recently, in 2025, the FDA approved Omisirge, the first allogeneic hematopoietic stem cell transplant therapy, for severe aplastic anemia [100,121].

MSCs, present in various tissues and organs, play crucial roles in tissue repair and regeneration by differentiating into specific cell types [122]. Stem cells survive much longer than normal somatic cells, and they are more likely to accumulate genetic mutations over time. Cancer research has shown that only a few mutations may be enough for a cell to lose control of the regular cell cycle and its self-renewal and growth, potentially leading to cancer [123].

Stem cells are responsible for and participate in normal development and health. Embryonic stem cells are the first producers of progenitors that determine how tissues and organs are arranged and form in the body. After these progenitor cells complete their work, they leave behind a guardian population of stem cells that repair each tissue when needed. Thus, these cells will undergo self-renewal and differentiate into specialized cells, allowing the gradual accumulation of mutations that lead to cancer, in line with current theories of the stem cell’s role in cancer development. Stem cells’ involvement might explain the difficulties of those treatments that aim to reduce tumor mass to cure cancer. This could simply be due to treatments targeting fast-dividing cells; thus, slow-dividing cells, like stem cells, might stay off target and thus untouched [124]. For this reason, cancer stem cells are believed to be responsible for resistance to chemotherapy and the recurrence of disease [112]. Therefore, a new treatment strategy is needed, particularly one that targets cancer stem cells in combination with current treatment approaches. A study by Markus Frank et al. first demonstrated this therapeutic strategy, which identified a class of stem cells that initiate melanomas in an animal model and, at the same time, an antibody that slowed tumor growth by targeting these stem cells [125]. An increasing number of studies are focusing on personalized medicine and targeted therapy as effective approaches to cancer treatment, with particular emphasis on stem cells due to their unique tumor-homing and anti-cancer properties [8,10]. Research has highlighted the multifaceted roles of mesenchymal stem cells (MSCs) in cellular functions, revealing their dual role as both promoters and suppressors of cancer [126]. Some studies suggest that MSCs can enhance tumor progression by facilitating angiogenesis and suppressing immune responses, thereby promoting tumor growth.

On the other hand, the tumor-homing properties of MSCs have been harnessed for their potential to serve as vectors for delivering anti-cancer agents directly to tumor sites. Furthermore, several studies have demonstrated MSCs’ ability to inhibit cancer proliferation and metastasis, primarily by inducing apoptosis [115,127]. Taken together, this duality underscores the complexity of MSCs in cancer therapy and their potential as tools for innovative therapeutic strategies.

Despite the recent advances, stem cell-based approaches should be rigorously evaluated to establish standardized, clear treatment algorithms and to provide safe, long-term outcome data. Notably, the efficacy and tolerability of stem cell-based modalities are modulated by variables such as patient age, comorbidity burden, disease stage, prior treatment exposure, donor- and tissue-source characteristics. These donor-specific variables could affect cell phenotype, morphology, and function. Moreover, the preparation and manufacturing processes for stem cell-based therapies also introduce additional heterogeneity. Thus, there is a need for comparative clinical studies, harmonized product characterization, and more precise patient-selection frameworks [128,129,130].

Furthermore, MSCs have been shown to produce extracellular vesicles (i.e., exosomes), which show exceptional potential as drug delivery vehicles due to their biocompatibility, low immunogenicity, and high loading capacity. These advantages promoted the exploration of non-cell-based therapies, particularly exosome-based approaches, as promising alternatives in cancer treatment [21,131,132]. For instance, an ongoing clinical trial (NCT03608631) is designed to assess the safety and efficacy of MSC-derived exosomes loaded with KrasG12D siRNA (iExosomes) for the treatment of pancreatic cancer. This highlights the potential of MSC-derived exosomes as innovative tools for targeted cancer therapy [133].

The development of resistance to both traditional chemotherapeutic agents and novel targeted drugs remains a significant challenge and a primary cause of cancer recurrence and mortality. Multidrug resistance refers to the ability of cancer cells to develop resistance to various structurally and functionally distinct cancer therapeutics. This can limit the efficacy of drugs and significantly alter the treatment response [135]. Drug resistance in cancer can arise due to several mechanisms, including genetic mutations, drug efflux pumps, altered drug metabolism, epithelial-mesenchymal transition (EMT), and a dense immunosuppressive tumor microenvironment (TME) [136,137,138].

Drug resistance was shown to be either intrinsic- existing before treatment or acquired -developed after therapy. Intrinsic resistance arises from genetic mutations present before treatment, variations within the tumor, or the activation of cellular defense mechanisms. As most tumors are multi-clonal and genetically heterogeneous, single-agent therapeutics often result in killing only the drug-sensitive cells, allowing the resistant cells to proliferate. Therefore, implementing combinatorial therapy strategies that target multiple driver genes or pathways simultaneously could reduce the risk of developing drug resistance during treatment [137].

On the other hand, acquired resistance arises from new mutations, alterations in the expression of drug targets, or interactions within the tumor’s microenvironment. These different forms of resistance may co-occur, making it critical to design more effective treatment strategies to minimize therapeutic failure. With advancements in next-generation sequencing technologies, genomic analysis before treatment and the adjustment of personalized therapies to prevent acquired resistance are vital for improving patient outcomes.

Traditional cancer treatment regimens have long involved the administration of the highest tolerable doses of drug(s), which led to faster drug resistance due to constant high-dose drug exposure to cancer cells, together with high toxicity and side effects. It has been reported that conventional immunotherapies may also cause severe side effects due to prolonged administration and hyperreactivity in some patients [139]. Nevertheless, this traditional treatment regimen is recently being replaced with intermittent dosing strategies -high and low dose switches- which have been shown to provide prolonged survival and delayed resistance [137].

Overall, while progress is being made in developing combination therapies and novel immunotherapy approaches, several challenges remain. For instance, the high complexity of tumor evolution and progression makes it more difficult to identify the best strategies to overcome drug resistance. Nevertheless, combination therapies generally provide better treatment outcomes compared to single-agent therapies, due to the heterogeneous and multi-clonal nature of tumors. In fact, the reason most single-agent therapies eventually lead to treatment failure is drug resistance, as these therapies selectively kill sensitive cancer cells, allowing the resistant cell population to proliferate and survive [137].

Hence, to improve cancer treatment outcomes with minimal side effects, a mechanistic understanding of an individual’s tumor and drug resistance mechanisms is necessary to develop enhanced treatment strategies. Significant advancements have been made in the field, including optimizing treatment combinations and doses, utilizing nanotechnology-based targeted delivery systems, etc. Moreover, to identify driver genes and molecules involved in tumorigenesis and drug resistance, utilizing the big data from high-throughput cancer genomics, proteomics, and metabolomics is critical and promising.

Along with technological advances in medicine and health sciences, cancer diagnosis has evolved in recent years. Early detection of cancer improves the chances of successful treatment and long-term survival. However, early-stage cancers are often asymptomatic and go undetected until they progress to advanced stages, where treatment options become less effective. Current screening methods face limitations in identifying cancers at their earliest, most treatable stages. To overcome this, there is an urgent need to develop more effective early detection tools, such as liquid biopsies, advanced imaging technologies, and reliable biomarkers, that can detect cancers before they advance. For instance, a recent study by Berahmand et al. developed a Nested Ensemble Deep Learning model for Gynecological Cancer Risk Prediction, demonstrating >98% accuracy on public benchmark datasets [140].

Alongside these technological advancements, it is also critical to address the significant disparities in access to cancer care. From a global health perspective, outcomes depend not only on scientific advances but also on timely access to screening programs, the availability of necessary infrastructure, and affordability. In low- and middle-income countries, these factors create additional barriers to appropriate cancer care. A cross-sectional study analyzed 36 cancer types across 185 countries and territories from the Global Cancer Observatory database. The authors demonstrated that the global cancer burden is expected to increase substantially by 2050. This increase is greater in low-Human Development Index countries, underlying the enlarging disparities in cancer outcomes and equitable access to prevention, diagnosis, and treatment worldwide [141]. Therefore, people in low- and middle-income countries may struggle with limited healthcare infrastructure, high costs of treatment, and unequal availability of therapies. Closing this gap requires investment in healthcare infrastructure, efforts to reduce treatment costs, and strategies to ensure equal access to life-saving technologies [142].

The genetic, epigenetic, and metabolic profiles of tumor cells often contribute to heterogeneity within the same tumor. Tumor heterogeneity is therefore used to describe variations among tumors of the same type across patients, the diversity of cancer cells within a single tumor, or differences between a primary and a secondary tumor [143]. Accumulating evidence suggests that a single tumor may contain clonally distinct populations, with no common driver gene alterations, making them difficult to treat and likely to develop resistance to therapeutics [144,145,146,147,148]. Hence, understanding the complex tumor pathophysiology and heterogeneity is vital for developing novel personalized cancer therapies.

Moreover, in metastasis, primary tumor cells spread to distant anatomical sites, posing an additional therapeutic challenge. These metastasized cancer cells exhibit greater phenotypic and molecular heterogeneity than the primary tumor. During metastasis, cancer cells undergo continuous genetic and epigenetic modifications, as well as contributions from the TME. These multiple adaptations drive more cancer cells to become more aggressive, invasive, and to foster therapy resistance. The anatomical and biological differences of metastatic lesions further complicate the treatment [149].

In addition, the dense, highly complex and heterogeneous nature of TME shaped by numerous cell types and tissues (i.e., immune cells, stem cells, blood vessels, and extracellular matrix components) further challenges cancer progression and treatment response. This dynamic TME significantly influences cancer progression and treatment response as the TME is involved in tumor initiation, growth and metastasis representing a challenge for developing effective anti-tumor strategies. For these reasons, there is an urgent need for more studies to fully understand how these interactions between the tumor and its TME contribute to cancer progression and therapy resistance. A deeper understanding could pave the way for innovative treatments targeting tumor cells and the TME, offering a more comprehensive approach to combat solid tumors [138].