What Happens Inside the Body During Radiation Therapy

The Physics-to-Biology Journey: From Beam to Molecular Hits

Radiation therapy begins with a beam whose purpose is deceptively simple: deposit energy inside a target volume. For external-beam treatments, high-energy photons are most common; electrons can be used for shallow targets, while charged particles like protons deliver energy more tightly with a pronounced Bragg peak. Inside the body, these beams do not “burn” tissue. Instead, they pass energy to molecules—especially water—causing ionizations and excitations over femtoseconds to microseconds. The immediate result is a storm of reactive species, most notably hydroxyl radicals, that diffuse a few nanometers and react with DNA, proteins, and membranes. In parallel, radiation can directly strike DNA, creating breaks in the sugar-phosphate backbone and altering bases.

The type and distribution of energy deposition matter. Photons at typical clinical energies interact mainly via Compton scattering, producing energetic electrons that leave clusters of ionizations in tracks. Protons and heavier ions deposit energy more densely near the end of their range, a property described by linear energy transfer (LET). Higher LET increases the probability of complex DNA damage—multiple lesions positioned so closely that repair machinery struggles to restore the original sequence. Oxygen amplifies these effects by “fixing” radical-induced damage into permanent lesions; this oxygen enhancement typically ranges around two- to threefold for many cell types, so hypoxic (oxygen-poor) tumor zones can be significantly harder to eradicate.

Key interactions that set the stage for biology include:
– Ionization of water molecules, spawning short-lived radicals that seek chemical partners within nanometers.
– Direct DNA hits, producing single- and double-strand breaks and base alterations in picoseconds.
– Track structure effects, where high-LET paths create dense, complex lesions with challenging repair requirements.
– Oxygen fixation, stabilizing radical-induced changes and reducing the chance of perfect repair.

By the time a patient has left the treatment room, the radiochemistry is essentially complete. Yet the clinical story is only beginning: over minutes to days, cells sense the damage, pause the cell cycle, attempt repairs, and choose survival or programmed death. The physics delivers the message; the biology decides how loudly it is heard.

DNA Damage and the Cell’s Decision Tree

Radiation’s biological signature is DNA damage paired with oxidative stress across cellular compartments. On average, one gray (1 Gy) of radiation can generate on the order of 20–40 double-strand breaks (DSBs) per cell nucleus, hundreds of single-strand breaks (SSBs), and thousands of base lesions. While SSBs and many base changes are repairable, DSBs—especially when clustered with other lesions—are the pivotal injuries that drive cell death or lasting mutations if misrepaired. The nucleus summons sensor proteins that recognize broken DNA ends, recruit repair complexes, and trigger checkpoints that slow or halt the cell cycle.

Cells employ two primary DSB repair pathways: non-homologous end joining (NHEJ) and homologous recombination (HR). NHEJ is fast, active throughout the cell cycle, and somewhat error-prone; HR is more accurate but restricted to late S and G2 phases when a sister chromatid is available as a template. The balance between these pathways depends on cell type, cell-cycle state, and the complexity of damage. Tumor cells often carry defects in checkpoint control or DNA repair genes, which can heighten sensitivity to radiation or, conversely, enable survival with mutations that confer treatment resistance.

After damage recognition, several fates are possible:
– Apoptosis: a tidy, programmed cell death that prevents spillover of inflammatory contents.
– Mitotic catastrophe: cells attempt division with unrepaired DSBs and fragment during mitosis.
– Senescence: a durable growth arrest paired with a pro-inflammatory secretory phenotype.
– Autophagy-mediated responses: recycling pathways that can be protective or, in some contexts, contribute to cell death.

Context shapes which fate dominates. Rapidly dividing tumor cells are vulnerable during G2/M, when condensed chromosomes make breaks particularly consequential. Well-oxygenated tumor regions suffer more fixed damage, while hypoxic pockets may evade lethal injury unless oxygenation improves between sessions. Normal tissues with robust DNA repair and slower turnover can tolerate sublethal hits—especially when dose is divided—yet some specialized cells (e.g., certain neurons) are sensitive to late consequences from vascular or glial changes rather than direct cell loss. Timescales vary: repair of many SSBs wraps up within hours, while DSB repair can stretch into a day or more, and misrepair scars—small insertions, deletions, or translocations—can persist indefinitely.

What makes radiation therapy clinically workable is this combination of damage specificity and biological triage. Dose, dose rate, and spatial distribution set a challenge that tumors, with their chaotic vasculature and genomic instability, often struggle to meet. Healthy tissues, aided by intact checkpoints and coordinated repair, are more likely to recover—especially when clinicians choreograph time between exposures to let them heal.

Why Fractionation Matters: The Four Rs and the Clock

Radiation therapy is typically delivered in daily fractions—often about 1.8–2.0 Gy per session, five days per week—over several weeks. This pacing is not convenience; it is biology in motion. Dividing the dose allows healthy tissues to repair sublethal damage, while tumors, which may be less proficient at faithful repair, accumulate injuries session by session. The framework known as the Four Rs captures the strategy: Repair, Reassortment (also called Redistribution), Reoxygenation, and Repopulation.

Repair: Between fractions, normal tissues mend SSBs and a portion of DSBs. Many repair processes have half-times on the order of hours, so a 24-hour rhythm provides meaningful recovery. Reassortment: Cells shuffle through the cell cycle; radiation tends to be more effective in G2/M and less in late S phase, so successive doses “catch” different cohorts at vulnerable moments. Reoxygenation: Tumor blood flow is uneven; after some cancer cells die or swelling subsides, formerly hypoxic zones can gain oxygen, increasing susceptibility to future fractions. Repopulation: Both tumors and normal tissues can regrow between sessions. Clinicians aim to exploit the first three Rs while keeping repopulation—especially of fast-growing tumors—in check.

The oxygen effect is among the strongest modifiers of response. Oxygen enhancement ratios commonly range around 2–3, meaning a hypoxic cell may require roughly double or triple the dose to achieve the same kill as a well-oxygenated one. Fractionation leverages reoxygenation to narrow that gap. The classic radiobiological model also distinguishes early-responding tissues (often higher alpha/beta values, tolerating larger fraction sizes) from late-responding tissues (lower alpha/beta values, where large per-session doses can increase long-term side effects). That is why conventional schedules favor modest daily doses, whereas highly conformal techniques may use fewer, larger fractions for precise targets after careful risk assessment.

Examples across practice show this logic at work:
– Conventional plans: 45–70 Gy total in 25–35 fractions for many solid tumors, balancing tumor control with normal tissue tolerance.
– Hypofractionation: moderately larger fractions over fewer visits for convenience and biological fit in select indications.
– Stereotactic regimens: very high precision and per-fraction doses (e.g., 8–20 Gy) for small, well-defined targets, trading fraction count for conformality and steep dose falloff.

Underneath the scheduling calendar is an elegant time-lapse of biology. Each fraction bruises tumor DNA and stresses its microenvironment; the night that follows is an opportunity for normal tissues to stitch themselves back together. The clock, in other words, is a treatment tool.

What Healthy Tissues Experience: Acute Responses and Late Echoes

No therapy is contained by lines on a planning screen; some dose inevitably reaches nearby organs. What those tissues experience depends on cell turnover rates, blood supply, and the cumulative and per-fraction dose. Acute effects reflect injury to rapidly dividing cell layers and local inflammation. Skin can redden as basal cells pause and vessels dilate; mucosal linings of the mouth, throat, or gut may inflame and ulcerate; hair follicles enter a reversible resting phase. These reactions often arise after 1–2 weeks of daily treatment, peak near the end of a course, and then resolve over several weeks as stem cells repopulate depleted layers.

Deeper organs display their own signatures. Bone marrow within the field can suppress blood counts; lungs may develop transient inflammation weeks to a few months after exposure; the heart and large vessels, when incidentally in the pathway, accumulate subtle endothelial changes that can influence long-term risk. The brain’s response is more about supporting cells and vessels than neurons themselves: transient swelling can cause fatigue or headaches, while months to years later, white matter changes or neuroendocrine shifts may emerge depending on the region exposed. The common thread is microvascular stress and immune signaling: cytokines rise, fibroblasts activate, and tissue architecture adapts.

Late effects arise when repair concludes not with a perfect restoration but with remodeling. Fibrosis can thicken connective tissue; small, fragile surface vessels may become more prominent; glandular tissues (such as salivary or lacrimal glands) can produce less fluid; and in rare circumstances, secondary malignancies can occur years later, reflecting the tiny fraction of misrepaired DNA events that persist. Dose-volume planning is designed to lower these risks by shaping beams around critical structures and setting thresholds that limit the portion of an organ receiving higher doses.

Supportive care reduces the intensity of these experiences:
– Gentle skin care, consistent moisturizing, and sun protection for exposed fields.
– Nutritional support, hydration, and symptom-guided medications for mucosal irritation or nausea.
– Breathing exercises and regular activity, as tolerated, to maintain lung function and overall stamina.
– Open communication with the care team to adjust plans and promptly treat evolving symptoms.

With thoughtful planning and modern imaging guidance, most effects are manageable and transient. Yet even when side effects resolve, body and mind remember the journey. A realistic expectation—mild to moderate fatigue, localized irritation, and temporary changes in taste or appetite for certain sites—helps patients prepare, and prompt reporting of new or worsening symptoms helps the team respond quickly.

Immune Ripples, Bystanders, and the Rare Abscopal Tale

Radiation is local by design, but its consequences can echo systemically. Damaged tumor cells release danger signals—known as DAMPs, including ATP and HMGB1—that alert nearby immune cells. Cytosolic DNA fragments in irradiated cells can trigger the cGAS–STING pathway, increasing type I interferons that recruit and activate dendritic cells. These sentinels process tumor antigens and present them to T cells, potentially sharpening immune recognition of malignant clones beyond the radiation field. This cascade helps explain why, in rare instances, tumors outside the treated area shrink after localized therapy—an observation dubbed the abscopal effect.

Two caveats keep expectations grounded. First, abscopal responses are uncommon without additional immune stimulation; they rely on an intricate choreography of antigen release, presentation, T-cell priming, and trafficking, all while the tumor microenvironment may be trying to suppress immunity. Second, lymphocytes are exquisitely radiosensitive, so unnecessary exposure of blood-rich areas can contribute to treatment-related lymphopenia, potentially dampening systemic immunity. Techniques that minimize dose to circulating blood and immune structures aim to preserve this partnership whenever feasible.

Bystander effects add another layer: cells not directly hit by radiation may still alter behavior after receiving chemical or vesicle-mediated signals from irradiated neighbors. These signals can promote survival, trigger stress responses, or, in some contexts, propagate damage. While intriguing, bystander biology is not a lever clinicians can reliably pull yet; it is part of the complex tissue conversation that follows dose delivery.

Practical implications include:
– Fraction size and timing can modulate immune signals; moderate per-fraction doses may favor antigen presentation while limiting excessive lymphocyte loss.
– Sparing major blood pools and lymphoid structures when possible may help maintain systemic immunity.
– Coordinated care that times radiation around other systemic treatments can support additive or synergistic responses without overwhelming normal tissues.

Think of the immune system as a patient ally that sometimes needs an invitation. Radiation can write that invitation by unveiling tumor antigens and sounding a local alarm. Whether the larger immune network attends—and how heartily it participates—depends on dose, field design, tumor biology, and the overall treatment plan.