Cancer – The Unequal War Between a Malignant Tumor and the Body

You may be wondering why this work was written and with what purpose. The answer is simple. For many years, I have been studying the origin of tumors, their characteristics, and therapeutic possibilities. One cannot help but notice that cancer cells behave like ruthless sociopaths with murderous tendencies. They build ever-growing cities (primary tumors), establish new settlements (metastases), and ruthlessly drain their country—the body—until they destroy it. I decided to describe the relationship between malignant tumors and the human body using military terminology. Let us consider a malignant tumor to be a rebel city (aggressor) and the body to be a state. For broader comprehensibility, I will include oncological terms and cancer-related knowledge in parentheses and italics.

What is the aim of this work? It’s not just about describing cancer in military terms and concluding that the analogy is indeed multifaceted. Warfare has a history stretching back thousands of years, whereas effective cancer therapy has only emerged in the last century. I abhor war, of course. But I asked myself—what if some strategy or tactic from the art of war could be applied in the fight against cancer? I validated this approach through discussions with a retired general (while on active duty, he likely wouldn’t have had time for me).

How Does This War Begin?

First of all, not immediately. A state usually exists for a long time (around 60 years) before a rebellion breaks out (cancer is often described as a disease of old age). There are exceptions (childhood cancers), but these are often due to lingering problems in the founding of the state (fetal development). During the state’s existence, due to external and internal causes (physical, chemical, and biological carcinogens), a number of behavioral and functional disorders typically accumulate in a single individual (4–7 mutations in a cell), eventually transforming them into a highly dangerous aggressor (a tumor gradually develops). This transformation can take several years, during which the individual is indistinguishable from others. They are likely not alone. Such transformations probably occur more often, and the state is usually able to eliminate these aggressors (immune surveillance, 3E theory). For an aggressor to break through, several factors are likely required—especially issues within the state (e.g., temporary immune suppression).

Why Call It an Aggressor?

There are many reasons. It’s a true sociopath. It begins to multiply—albeit at half the speed of its healthy peers—but it keeps going. Unlike the law-abiding citizens of the state, it does not follow any rules of collective living. A typical citizen respects their surroundings and the territorial rights of others. They build a family, but stop multiplying when they encounter neighbors (contact inhibition of proliferation). Not our sociopath. It continues reproducing and forms a growing city (tumor). Once this initially small city reaches a certain size (1 mm³), the descendants living within it begin facing shortages in supply (nutrients) and oxygen. It’s a paradox—despite hardly using oxygen even when it is available (Warburg effect), in panic at the risk of suffocation, they send out desperate cries for help (hypoxia-inducible factor, HIF). The state begins to build a supply network (tumor vascularization), which the rebel city controls itself (VEGF growth factor). Nutrients and oxygen begin flowing into the rebel city (tumor). Instead of fully utilizing these resources (aerobic glucose metabolism yielding 38 ATP), the rebels take a bite of food and spit out the rest (lactate). They use only one-nineteenth of the energy in food (2 ATP). The rebel city grows, but drains the state, which begins to waste away (cachexia). The rebels attract normal healthy people from nearby, employing them in logistics and supply (vascularization) and in construction (stroma). The city becomes highly diverse, and the influx of people from surrounding areas helps deceive the state into thinking nothing is wrong. The rebels employ many such tricks, which will be described further.

Rebels’ Tricks

Rebel cities (various tumor types) have no central leadership or organization; they are gangs of bandits with little in common. Still, they share some features. Interestingly, these traits are also shared with the founding pioneers of the state. In a hostile environment (the womb), those pioneers fought for survival under dire conditions, where they risked being destroyed (rejection of the semi-allogeneic graft—since the fetus is half foreign, from the father). To survive, they burrowed into the land (blastocyst implantation), consumed the soil (histotrophé), and later subjected the land to their service (placenta formation). They battled the local army (maternal immune system) using tactics to suppress the defense (TGF-beta, IL-10 cytokines). They even sent out raiding parties to suppress enemy resistance far away (e.g., alleged trophoblast metastasis to the lungs to induce tolerance; reproductive and cancer immunity appear to be one and the same).

The rebelling inhabitants (tumor cells) have recalled all these capabilities. The information is already stored (in genome). Now, after a long period of peaceful development, the rebels have emerged from within the state—they are its own citizens, just slightly altered—and it becomes easy for them to survive. And so they do. Who would harm them? But they grow, plunder, establish new settlements (metastases), drain the state, destroy it—and with a likelihood greater than 150,000:1, they succeed in bringing it down. They perish with it, but no one ever told them that. And even if they had, it wouldn’t matter. They are not a separate biological species; they always reemerge. Unlike parasites, which learn to spare their hosts to avoid dying with them (natural selection), tumors never learn. Parasites may evolve toward symbiosis—cancer never does.

The State Strikes Back – or Tries To

Fortunately, rebels are not entirely indistinguishable from other citizens (they carry newly formed antigens—neoantigens). They can’t be—those mutations must show. So the state notices and begins the war (immune response). The worst part is that no matter what resources the state uses (innate and adaptive immunity), the rebels (tumors) always seem to win. How?

First, the rebels remain hard to detect. They hide among recruited citizens from the state. Even if the army (immune system) spots them and mobilizes troops that recognize and attack them, the rebels have a clever trick. They know they will be identified by their distorted faces (tumor antigens). But the attacking soldiers check their ID cards (MHC I molecules, found on all cells except red blood cells) before striking. Knowing this, the rebels hide their ID cards (downregulate MHC I), so the soldiers pass by without taking action.

But the army isn’t foolish. It has special troops (natural killer cells, NK cells) trained to attack intruders without ID. However, the rebels have another trick. They keep the original ID hidden but pull out a fake passport (HLA-G molecules), which reliably protects them from these troops as well. Thus, the state’s army roams the battlefield in vain—not only failing to stop the rebels, but even unintentionally helping them. The rebels enslave parts of the state’s army to produce drugs (cytokines) that support their carefree lifestyle.

Sometimes, the state’s troops kill off some rebels who failed to hide well. They might even wipe out most of the city. But since the rebels lack essential institutions (organs), this has no effect. It simply selects for those who are so similar to citizens that they go undetected. These less conspicuous yet equally aggressive individuals rebuild an even stronger and larger city on the ruins.

The Rebels’ Arsenal

Rebels don’t rely solely on camouflage as their weapon against the state’s army (the immune system). They possess dozens of highly effective systems. One of them is active ideological subversion (immunosuppression), leading to a state of tolerance where the city is accepted and all attacks cease. The rebels send out special signals (TGF-beta cytokine) that transform commanding officers (CD4+ T cells) into completely different types of soldiers (CD4+, CD25+FoxP3+ Tregs—regulatory lymphocytes). These transformed officers begin broadcasting the same message, accelerating their own proliferation (autocrine loop). They also act directly—both through signals and contact—on fellow soldiers (CTLs, NK cells), convincing them to stand down (immunosuppression) and tolerate the enemy (immune tolerance).

This is a very effective method, but not the only one. The rebels can, for example, hide under piles of shells fired by the enemy (antibody masking), induce suicide in enemy soldiers (apoptosis), and more.

Rebels continuously expand their city—sometimes pausing, but always resuming. Their aggressive expansion damages the state and may destroy it entirely. To achieve this, they deploy demolition machines that crush everything in their path (metalloproteinases, serine, cysteine, and aspartate proteases). Since these machines are also vital for the state’s industry, destroying them indiscriminately is not a viable option.

A Highly Dangerous Expansion

The greatest danger to the state is that rebels are not very attached to their hometown (loss of adhesion molecules like cadherins and integrins) and easily break free. Using their demolition tools, they overcome obstacles (basal lamina) and begin founding distant settlements (metastases). For transportation, they exploit the state’s supply network, which they’ve extended into their city (blood or lymphatic vessels). They ride these networks to distant regions that “smell” right to them (chemotaxis). After attaching to the vessel wall, they must crawl through it using their proteases and make their way to a site where they found a new settlement. This settlement eventually becomes a city, from which new colonists depart (metastasis of metastases). The state tries to destroy each new outpost, but with each one, it loses more vital components (organs) and eventually collapses from total exhaustion (cachexia). The state is defeated (the person dies of cancer).

What Can Be Done?

Luckily, powerful superpowers exist that can help the state (oncologists). Still, they can’t do everything—only about half of all states are saved. Primarily, they succeed in those where no new settlements have yet been founded (non-metastatic cancers). Once metastasis has occurred, the chances of help drop to about 10%.

What Weapons Do the Superpowers (oncologists) Use – And With What Success?

Total destruction of the city from the ground up (surgical removal) – this is the most fundamental and crucial approach.
The problem is that someone may be hiding deep in the basement, and the city may regenerate (recurrence). A serious issue arises if settlements (metastases) already exist at the time of the city’s destruction. Sometimes these settlements start growing rapidly after the primary city is removed. The reason is unclear – possibly because their ability to evade the state’s army increases (surgery-induced immunosuppression).
Radiation and chemical attacks (radiotherapy and chemotherapy) – harm not only the aggressors but also the state’s citizens.
The strategy assumes that although aggressors multiply more slowly than normal cells, the state can recover more quickly from an attack that destroys both. By alternating attack and rest, the number of aggressors can be reduced until they are eliminated. However, this damages the state significantly. Dormant aggressors are hard to kill. Moreover, in chemical attacks, the aggressors use powerful systems to eliminate the poison from their bodies (e.g., P-glycoprotein).
Over time, resistant individuals among the aggressors survive and proliferate. Drugs that affect aggressors more than normal cells are rare. There are few major metabolic differences (except more anaerobic metabolism in tumors – Warburg effect – and higher sensitivity to glutamine metabolism inhibitors).
Biological attack – this approach is based on the idea that aggressors (tumor cells) are less capable of defending against certain pathogens (e.g., Newcastle disease virus). These pathogens may kill them or mark them so that the state’s soldiers can recognize them. This strategy is still experimental and not consistently effective.
Strengthening the state’s defenses (immunotherapy) – the state (body) has a vast, trained army (immune cells). As we’ve discussed, the enemy (tumor) has many tricks for hiding and defending itself. One idea was to unleash the army completely by removing all restraints (checkpoint inhibitors block the immune system’s brakes). This tactic worked, and in 2018, its inventors (J. P. Allison and T. Honjo) received the Nobel Prize.
Unfortunately, it only works for 8 out of 100 types of cities (cancer types) – those where enemies are more easily recognized (more antigenic mutations). Even there, full victory is achieved in only about 20% of cases, and side effects are significant. Overstimulated soldiers begin killing indiscriminately – even the state’s own harmless citizens (autoimmune disease).
Destroying demolition machines (inhibiting proteases involved in invasion) – as mentioned, since the state needs these machines too, non-targeted attacks haven’t been successful.
Ideological re-education (differentiation therapy) – the goal is to turn rebels into law-abiding citizens. When re-education is done on prisoners (in vitro), it works. In the city itself, it’s hard to achieve the necessary level of ideological influence (concentration of differentiating substances).
Eliminating traitors (regulatory T cells, Tregs) – using specific agents (TGF-beta), rebels convert some of the state’s soldiers (CD4+ T cells) into traitors (Tregs), who persuade other soldiers—through contact or chemicals – that the aggressors are also human and should be left alone (tolerance). Eliminating these traitors must be targeted to the city, as they are essential elsewhere in the state to prevent soldiers from mistakenly attacking their own (autoimmunity).
Trojan horses – the city’s newly formed pipelines (blood vessels) are full of holes. This allows drugs to be attached to large packages (carriers). These are too big to penetrate normal tissue but can enter the city. The drugs are bound so they are inactive during travel. Once inside the city, the rebels’ demolition tools (proteases) release the active drug. But this is not perfect – some drugs leak and damage the state.
Starving the city – this approach is more experimental (alternative medicine). Since the state also needs food, local starvation is difficult. More promising is cutting off the supply routes (ligatures) or inhibiting the city’s supply line construction (anti-VEGF therapy).
Feigning retreat and sudden ambush (immunosuppression followed by stimulation – not yet in use) – a fake retreat (immunosuppression) removes soldiers from around the city, preventing the emergence of traitors (Tregs from CD4+ cells). With no pressure, rebels stop hiding their ID (MHC I) or producing fake passports (HLA-G). A swift return of the army may prove highly effective, especially with rested troops. (This has been observed in parasitic infections).
Inciting internal conflict – though this would be elegant, it is hard to achieve at the cellular level.

Our Approach (Our Comprehensive Cancer Immunotherapy)

Our team chose a different tactic. First, we decided to mark the enemy so that they could never hide again and would be clearly visible. We dropped a paint bomb into the enemy city (injected tumors with a solution of mannan equipped with the BAM anchor, which labels cells with mannan and activates complement molecules C3b/iC3b)…

We mixed the paint with various scents that powerfully attracted first-line fighters from across the state… (MBTA contain mannan-BAM, three TLR agonists, and anti-CD40 antibody).

After receiving this news, second-line fighters (CTL lymphocytes) immediately went not only to the enemy city (tumor), but also to the whole country… (immune memory).

Our Goal

Our current mission is to obtain all the bomb components in such quality that they cause minimal harm to surrounding civilians. Everything must be manufactured with utmost care, following Good Manufacturing Practices (GMP-grade chemicals)…

If everything goes well, the state’s high command (SÚKL), or the EU (EMA), or even NATO (FDA), will grant authorization… That is our hope too—because our devious enemy (cancer) kills 10 million people each year, and projections show that number will only grow.

Let us unite and defeat this enemy.
Jan Ženka