How Wounds and Cancers Heal — and What Happens When They Don’t (Part 1)
When we speak casually about healing, we usually mean repair: the closing of a cut, the knitting of a bone, the disappearance of pain. Biologically, however, healing is something far more specific and far more demanding. It is not simply the activation of repair mechanisms, but their completion. It requires not only construction, but dismantling; not only inflammation, but its active resolution; not only growth, but the disciplined withdrawal of growth.
In healthy tissue, injury triggers a tightly choreographed sequence of events that unfolds over time and then—crucially—stops. This stopping is not passive. It is not the fading of signals due to exhaustion. It is an active, genetically programmed transition from danger to stability. When this transition fails, the tissue does not remain neutral. It becomes pathological.
Chronic wounds are the clearest demonstration of this principle. They are not inert lesions. They are biologically overactive, metabolically demanding, inflammatory environments locked into a perpetual attempt at repair. The wound does not close because the system does not know how to finish.
This distinction—between activation and resolution, between repair and healing—is essential. Without it, the idea that cancer might resemble a non-healing wound remains metaphorical. With it, the analogy becomes mechanistic.
The Overview
Healing is an Active Process of Resolution, Not Just Repair: Biologically, healing is distinct from repair. Repair is the activation of construction and inflammation, but true healing requires the active resolution, dismantling, and disciplined withdrawal of these programs, essentially providing a genetically programmed "stop" signal to achieve stability. When this critical transition from danger to stability fails, the tissue becomes pathological, as seen in chronic wounds.
Chronic Wounds are Repair Programs That Cannot Terminate: Conditions like diabetic ulcers are not deficient in repair signals; they are saturated with them, stuck in a biologically overactive, perpetual state of attempted repair. The fundamental failure is that the system does not know how to finish, characterized by persistent inflammation, elevated proteases, and accumulation of uncleared cellular and matrix debris.
Resolution is the Most Overlooked Phase of Tissue Recovery: Successful healing hinges on the "Resolution" phase, which is an active biological program governed by specialized pro-resolving mediators like resolvins. These molecules actively reprogram immune cells—shifting macrophages from pro-inflammatory to reparative states—to actively dampen signaling, clear apoptotic cells (efferocytosis), and regress excess blood vessels and temporary matrix.
Cancer is Understood as Pathological Repair: The analogy of tumors as "wounds that do not heal" is mechanistic, suggesting that malignancy is an "emergent property of unresolved repair" rather than solely a cellular rebellion. Tumors are self-reinforcing tissue ecosystems where native repair programs (growth, inflammation, remodeling) are continuously re-initiated and sustained indefinitely, transforming repair into the disease itself.
The Tumor Microenvironment Functions as a Permanent Wound Bed: Only a fraction of a tumor is cancer cells; the rest is a complex microenvironment that mimics a chronic wound bed. It is defined by persistent high levels of inflammatory cytokines, growth factors, and continuous remodeling of the extracellular matrix. Unlike in normal wounds where these signals decay, they do not resolve in the tumor environment.
Cancer-Associated Fibroblasts (CAFs) are Trapped Repair Cells: Fibroblasts, essential for wound scaffolding, migrate and deposit matrix during repair but normally deactivate once healing is complete. In tumors, these cells become CAFs, which are non-malignant repair cells that never receive the signal to stop, leading them to stiffen the tissue and create structural barriers that support tumor growth and invasion.
Tumor Vasculature is an Example of Angiogenesis Without Maturation: While tumors are highly vascularized, the blood vessels remain permanently immature, tortuous, and leaky, leading to persistent hypoxia despite high vessel density. This structural abnormality is seen as a repair program—the sprouting of new vessels—that is stuck in an early phase, failing to regress or mature into stable, functional structures.
Immune Infiltration is Misdirected Repair Biology: Tumors are infiltrated by immune cells, but effective clearance fails because macrophages and other immune populations become dysfunctional. They often adopt inflammatory or suppressive phenotypes that sustain tissue remodeling and inhibit immune attack, mirroring the dysfunctional macrophage behavior seen in chronic wounds that fail to complete efferocytosis.
Persistence of Debris Drives the Non-Healing State: The central answer to why repair programs cannot terminate lies in the persistence of molecular debris, including dead cells, damaged matrix fragments, and un-cleared DNA-based material. The presence of this debris continuously provides the system with the signal that injury is ongoing, creating a self-sustaining loop where injury begets repair, and repair begets more injury.
Therapeutic Strategies Must Account for Resolution: Understanding cancer through this lens changes the therapeutic question from only how to eliminate malignant cells to how to stabilize the tissue environment. Any cancer therapy that focuses only on killing cells but ignores the process of resolution—specifically, the cleanup of debris and the calming of inflammation—is incomplete, as cell death itself can generate the debris that fuels the non-healing, pro-malignancy environment.
The Architecture of Normal Wound Healing
Wound healing is often described as a sequence of phases, but this description can be misleading if it suggests a rigid or linear process. In reality, healing is a dynamic overlap of programs, each of which must be initiated and then actively silenced.
The initial phase, hemostasis, is mechanical and biochemical. Platelets aggregate, clotting cascades activate, and bleeding is controlled. But platelets are not passive plugs. They release growth factors and cytokines that set the stage for what follows.
Inflammation comes next, and it is here that misunderstanding often begins. Inflammation is not a mistake, nor is it a problem to be suppressed. It is an essential biological response that recruits neutrophils and macrophages to the site of injury. These cells clear pathogens, digest damaged tissue, and release signals that mobilize repair.
At this stage, the tissue environment is hostile by design. Reactive oxygen species are generated. Proteases degrade extracellular matrix. Cytokines amplify immune signaling. From a distance, this looks destructive. Locally, it is purposeful.
The proliferative phase follows. Fibroblasts migrate into the wound bed and deposit provisional extracellular matrix. Endothelial cells sprout new blood vessels, forming a dense but temporary vascular network. Epithelial cells proliferate to cover exposed surfaces. This is a phase of construction, but it is provisional construction—fast, flexible, and intentionally imperfect.
What distinguishes successful healing from pathology lies in what comes next.
Resolution: The Most Overlooked Phase of Healing
Resolution is not simply the absence of inflammation. It is an active biological program with its own signaling molecules, transcriptional changes, and cellular behaviors. Over the past two decades, work by Charles Serhan and others has demonstrated that resolution is governed by specialized pro-resolving mediators—resolvins, protectins, maresins—derived from polyunsaturated fatty acids. These molecules do not suppress immunity; they reprogram it.
Macrophages, which initially adopt pro-inflammatory phenotypes, shift toward reparative states. They increase efferocytosis—the engulfment of apoptotic cells and debris—and, in doing so, actively dampen inflammatory signaling. Neutrophil recruitment stops. Existing neutrophils undergo apoptosis and are quietly cleared. Cytokine gradients collapse.
At the same time, angiogenesis is actively reversed. Excess vessels regress. Fibroblasts deactivate or undergo apoptosis. Provisional extracellular matrix is remodeled into mature, mechanically stable tissue. Scar formation is not a failure of healing; it is evidence that healing has ended.
This finality is not accidental. It is essential. Tissue that remains in a repair state is unstable, energetically costly, and vulnerable to further injury.
Chronic Wounds: When Healing Programs Cannot Terminate
Chronic wounds illustrate what happens when resolution fails. Diabetic ulcers, venous stasis ulcers, and pressure sores are not deficient in repair signals. On the contrary, they are saturated with them. Inflammatory cytokines remain elevated. Proteases continue to degrade matrix. Angiogenesis persists but produces fragile, dysfunctional vessels. Fibroblasts remain activated yet ineffective.
Crucially, these wounds are characterized by persistent debris. Dead cells, degraded matrix fragments, and inflammatory mediators accumulate faster than they are cleared. Macrophages become dysfunctional, trapped in inflammatory phenotypes. Efferocytosis falters. The wound environment becomes self-sustaining.
In this state, the tissue is not failing to heal because it is inactive. It is failing because it is stuck.
Tumors and the Signature of Non-Resolution
When pathologists began comparing tumors to wounds, they were struck by familiar patterns. Tumors are highly vascularized, yet poorly perfused. They are infiltrated by immune cells, yet immune clearance fails. They are rich in fibroblasts, yet tissue architecture remains chaotic. They are inflamed, yet never resolve.
Harold Dvorak’s formulation—tumors as wounds that do not heal—was initially grounded in histology and physiology. Tumors looked like granulation tissue frozen in time. What was missing was a molecular explanation for why the “stop” signal never arrived.
That explanation is now coming into focus.
Why Resolution Matters More Than Restraint
A key misunderstanding in both wound care and oncology has been the belief that pathology arises primarily from excessive activation. This leads naturally to strategies focused on suppression: anti-inflammatory drugs, immunosuppressants, cytotoxic therapies.
But chronic wounds teach a different lesson. The problem is not that repair is too strong. It is that resolution is incomplete.
Inflammation that cannot resolve does not simply persist; it mutates. Immune cells shift into dysfunctional states. Fibroblasts become fibrotic. Vessels become abnormal. The tissue environment begins to select for cells that can survive chaos.
This insight is critical for understanding cancer. If tumors arise and persist in environments where injury signals never clear, then malignancy is not merely a property of cells, but of context.
Cells that would otherwise undergo apoptosis, differentiation, or immune clearance may instead adapt, exploit, and eventually dominate a chronically injured niche.
The Implication: Cancer as a Failure of Healing, Not Just Growth
Seen through this lens, cancer begins to look less like a rebellion and more like an emergent property of unresolved repair. Genetic mutations matter, but they are filtered through tissue environments that reward certain behaviors and punish others.
In a stable, well-resolved tissue, aggressive, proliferative cells are often eliminated. In a chronically inflamed, debris-filled environment, those same traits may confer survival advantage.
This reframing does not deny the importance of genetics. It contextualizes it.
Cancer may represent what happens when the body’s most powerful survival programs—repair, inflammation, adaptation—are activated without an exit.
Why This Matters for Everything That Follows
If healing requires resolution, and if tumors resemble wounds that never resolve, then any cancer therapy that ignores resolution is, by definition, incomplete.
Killing cells without addressing debris risks perpetuating injury. Suppressing inflammation without enabling cleanup risks stagnation. Normalizing tissue architecture without calming the underlying damage risks collapse.
Before we can meaningfully discuss cancer treatment, we must therefore understand wound healing not as a metaphor, but as a template.
In the essays that follow, we will examine how cancer therapies intersect—often unintentionally—with each phase of healing. We will see how cell death generates debris, how debris sustains inflammation, how inflammation distorts immunity, and how normalization can restore order without destruction.
But none of that makes sense unless one first accepts a simple, unsettling premise:
Healing is not what happens when damage stops.
Healing is what happens when repair is allowed to end.