1. Introduction

Cancer continues to be a public health burden being the second leading cause of death in the United States from 2019 to 2023. In 2019, it caused 597,086 deaths, and by 2023, there have been 613,331 deaths due to cancer[1]. While the eyes of the public turned to the COVID-19 pandemic in 2021, cancer once again regained its status in 2022 and 2023, with several hundred thousand annual deaths [1]. These startling figures highlight flaws in how cancer is treated, even after decades of research and new treatments.

Over the years, conventional treatments of cancer have involved surgery, chemotherapy, and radiation, all with harmful side effects and varying levels of success aross different cancer types. Even though targeted therapies and immunotherapies have emerged as new treatment paradigms, inherent and/or acquired resistance, toxicities, and limited applicability remain crucial concerns. One important disadvantage of existing approaches is the insufficient exploitation of the diverse vulnerabilities of cancer cells through rationally designed drug combinations.

This paper will address that knowledge gap by discussing the biological hallmarks of cancer cells that can be synergistically targeted, along with promising emerging compounds and techniques that are not yet widely used in clinical practice. It aims to provide a framework for designing next-generation combination therapies with greater efficacy and reduced toxicity.

2. Targeting hallmarks of cancer cells

2.1. Uncontrlled proliferation and apoptosis evasion

Cancer cells behave very differently from healthy ones, and those differences can be used against them in treatment. One significant distinction is their tendency to divide uncontrollably — they ignore the standard signals that tell a cell when to grow or stop. Because of this, drugs that disrupt the cell cycle, like CDK inhibitors, can be particularly effective [2]. Another trait of tumor cells is their ability to dodge cell death, even when damaged. Typically, overly stressed or mutated cells undergo apoptosis - a self-destruct sequence. Nevertheless, cancer cells often escape this fate. To counter that, researchers have found that drugs that trigger apoptosis alongside traditional chemotherapy can make treatments more successful by ensuring that the cancer cells do not survive [3].

2.2. Altered metabolism: the warburg effect

Cancer cells also do not make energy the way healthy cells do. Instead of undergoing normal oxidative phosphorylation, they often switch to a faster, less efficient process called aerobic glycolysis — even when plenty of oxygen is available. Scientists call this the Warburg effect [4]. At first glance, it seems strange since it does not produce as much ATP. However, this shortcut helps the cells keep up with the intense energy and resource demands caused by their rapid growth. Because of this metabolic quirk, researchers have looked into targeting it directly. One drug that's shown promise is metformin, a common diabetes medication. It has been getting attention in cancer research because it interferes with mitochondrial complex I, cutting down on ATP production and slowing cancer cell growth in some case[5]. So, something as ordinary as a diabetes drug might become part of the cancer-fighting toolbox.

2.3. Genomic instability and DNA repair defects

Another hallmark of cancer is genomic instability. Defective DNA repair mechanisms in cancer cells make them highly sensitive to treatments such as PARP inhibitors, especially when combined with agents that cause further DNA damage [6]. Finally, evading immune responses is another way tumor cells suppress anti-tumor responses. For these reasons, therapies that include immune checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies combined with other forms of therapy, have opened up new avenues for reactivating the immune system against tumors [7]. Features like those identified here provide the backbone for targeted combinations of drugs aiming at multiple vulnerabilities simultaneously.

3. Emerging and underutilized therapeutic approaches

The development of new anti-cancer therapies increasingly focuses on emerging compounds and methods that, while not yet widely adopted in clinical practice, show immense potential. Among the most important are metabolic modulators, ROS-based therapeutic approaches, natural compounds, ion channel modulators, immune function enhancers, and innovative techniques such as DNA origami for precision targeting purposes.

3.1. Metabolic modulators

Some cancer treatments currently being studied by disrupting how cancer cells make and use energy. AICAR is one such agent—it activates a cellular energy checkpoint called AMPK. Once activated, it slows cell growth by blocking the production of materials needed for cell proliferation[8]. This is a big deal for cancer since those cells are always trying to grow fast. Another class of agents, PKM2 inhibitors, targets a key enzyme used in glycolysis— the quick-energy pathway favored by cancer cells. Blocking this enzyme makes it harder for tumors to sustain their growth [9]. More recent attention has focused on compounds like nicotinamide riboside (NR) and NMN. These are precursors of NAD+, which helps power the mitochondria—the part of the cell responsible for energy. Some research suggests that boosting NAD+ can help restore normal energy regulation in cancer cells and potentially slow them down [10].

3.2. Ros-based therapies

Other new approaches work by overwhelming cancer cells’ ability to manage oxidative stress. Some therapies, like β-apache, raise reactive oxygen species (ROS) levels inside cancer cells. If ROS is boosted enough, the cancer cells cannot cope and self-destruct [11]. Another example is MitoPQ, which goes straight for the mitochondria. It causes oxidative stress in the tumor's energy center but does not mess with healthy cells as much [12]. These treatments offer a new angle — instead of directly killing cancer cells with toxins, they push the cells past their limit by hitting weak spots in how they manage metabolism and stress.

3.3. Natural compounds

Plant-based compounds are also gaining interest for their roles in cancer therapy. Curcumin — the compound that gives turmeric its yellow color — and resveratrol — found in things like red grapes and berries — have both been studies for their anti-cancer effects. Researchers have found that these molecules can interfere with signaling pathways and even induce apoptosis, basically the programmed cell death process [13][14]. Resveratrol also affects metabolism by turning on sirtuins, a group of enzymes linked to DNA repair and how cells manage energy. The downside? Neither of them absorbs very well in the body, which kind of limits how useful they are right now. That is why scientists are trying to develop better ways to deliver them [13]. Berberine is another interesting one — it has been shown to inhibit cancer cell proliferation by disrupting cellular metabolism [15]. If researchers can determine how to enhance the effectiveness of these compounds within the body, they could pave the way for treatments that are less taxing on patients and more accessible than many existing therapeutic options.

3.4. Ion channel modulators

There is also some interesting early research around ion channels — the little gateways in cells controlling calcium flow. One group that's getting attention is TRP channels (short for transient receptor potential), which help regulate how calcium moves inside cells. Since calcium signaling is tied to how cells grow and spread, messing with these channels in cancer cells could reduce their ability to multiply or move to other body parts[16]. This is still an early-stage area of research, but it shows how scientists are starting to think outside the box — looking at parts of cancer cell biology that have not been tapped for treatment yet.

3.5. DNA origami and targeted delivery

A novel and particularly creative direction if the use of DNA origami. In this approach, DNA is folded into precise 3D shape that can carry druges directly to cancer cells.The cool part is how targeted it is. Instead of blasting the whole body with chemo, these folded DNA pieces can carry drugs exactly where they need to go, which means healthy cells mostly get left alone. That is a big deal, especially considering how rough the side effects of standard treatments can be. Linking drugs or immune molecules to these DNA structures also looks like it helps cut down on the stuff ending up in the wrong place [17]. People are putting more thought into cancer treatments that are not just one-size-fits-all. The idea is to make them more personal, based on the specific traits of someone's tumor. One thing that's come up a lot in research is figuring out how to get the immune system more involved.

3.6. Immune modulators beyong checkpoints

There is a particular pathway called STING that seems to help with that. When it is turned on, it boosts the immune system by getting specific cells — dendritic cells — to wake up and bring in T-cells, which are the ones that go after cancer [18]. Another method researchers have looked into is stopping an enzyme called IDO1 — which stands for indoleamine 2,3-dioxygenase. It usually works by slowing down how T-cells act, and that is not ideal when the goal is to get the immune system to attack cancer. By blocking this enzyme, immune response can be restored. These therapies are often used with checkpoint inhibitors to make the treatment more effective [19]. These new compounds and strategies are an exciting direction in the innovation of cancer therapy. This will probably allow investigators to combine these new strategies into new drug combinations that more effectively treat the complexity of cancer biology and ultimately benefit patients.

4. Conclusion

Rationally designed drug combinations offer the future for cancer therapy because they can overcome resistance, enhance efficacy, and minimize toxicities. Understanding cancer biology, emerging compounds, and innovative approaches is creating the path to a new generation of anti-cancer therapies. Continued investment in this area will be required to achieve the ambition that cancer will be a manageable or curable disease.