Noninvasive Physical Stimulation Reprograms Tumor Macrophages for Cancer Immunotherapy

Cancer researchers are turning to an unexpected set of tools—sound waves, beams of light, electrical pulses, magnetic nanoparticles and carefully calibrated radiation—to reprogram the immune cells that help tumors survive. A review in Bioengineering & Translational Medicine argues that these non-invasive physical stimulation technologies could become a new class of macrophage-targeted immunotherapy, converting the tumor microenvironment from an immune sanctuary into a site where cancer can be recognized and attacked. The strategy focuses on tumor-associated macrophages, or TAMs, which can account for a substantial share of the immune cells inside many tumors. Rather than trying only to kill cancer cells directly, the proposed treatments use externally delivered energy to alter the biological instructions received by TAMs, potentially strengthening the effects of checkpoint inhibitors and other immunotherapies.

TAMs are not a single, uniform cell type. They occupy a spectrum of functional states shaped by cytokines, metabolites, oxygen levels, acidity, mechanical forces and signals released by cancer and stromal cells. At one end are M1-like macrophages, which respond to inflammatory cues such as interferon-γ and tumor necrosis factor-α. Through pathways including JAK–STAT1, NF-κB and IRF5, these cells increase production of inflammatory mediators, nitric oxide and antigen-presentation machinery. They can help recruit CD8-positive cytotoxic T cells and natural killer cells. At the other end are M2-like programs, promoted by interleukins 4, 10 and 13, transforming growth factor-β and colony-stimulating factor 1. Signaling through STAT3, STAT6, PPARγ and PI3K–AKT–mTOR drives tissue repair, blood-vessel growth and immune suppression. In real tumors, macrophages rarely fit neatly into either category, but the M1/M2 framework remains useful for describing opposing immune functions.

The cancer-promoting side of this plasticity is extensive. M2-like TAMs can release epidermal growth factor, transforming growth factor-β and platelet-derived growth factor, supporting tumor-cell survival and proliferation. They produce matrix metalloproteinases and cathepsins that break down collagen and basement membranes, opening routes for invasion. They also secrete vascular endothelial growth factor, basic fibroblast growth factor and interleukin-8, encouraging the formation of abnormal blood vessels that feed the tumor and provide escape routes for metastasizing cells. Meanwhile, interleukin-10, transforming growth factor-β, PD-L1 and other suppressive signals blunt cytotoxic T cells and natural killer cells while attracting regulatory T cells and myeloid-derived suppressor cells. TAMs can even help maintain cancer stem-cell niches and interact with nerves, creating feedback loops that reinforce malignancy. Reprogramming them could therefore remodel immunity, blood vessels, extracellular matrix and tumor metabolism at the same time.

That possibility is especially attractive because tumors are difficult places for conventional drugs to reach. Dense stromal tissue, abnormal vasculature, low oxygen, acidic pH and high interstitial pressure can prevent therapeutic molecules from distributing evenly. Systemic cytokines, gene therapies and macrophage-directed drugs may also affect healthy tissues or lose effectiveness as tumors adapt. Physical stimulation offers a different mode of access: energy can be focused or applied repeatedly, with variables such as intensity, frequency, wavelength, pulse duration and temperature adjusted to the target. The review describes this as a controllable interface between engineering and immunology. Mechanical stress may open ion channels; light can excite sensitizers or alter redox chemistry; electric fields can change membrane permeability; magnetic particles can generate heat or release iron; and radiation can provoke immunogenic cell death. These inputs ultimately converge on the same inflammatory networks that govern macrophage behavior.

Light-based therapies illustrate both the promise and the engineering challenge. Photodynamic therapy activates a photosensitizer to generate reactive oxygen species, damaging tumor cells and inducing immunogenic cell death. That process can expose calreticulin, release ATP and liberate HMGB1, danger signals that alert dendritic cells and macrophages. Conventional type II photodynamic therapy depends heavily on molecular oxygen, making it vulnerable to the severe hypoxia found in solid tumors. Newer type I systems generate radicals such as superoxide and hydroxyl radicals under oxygen-poor conditions, while some nanoplatforms produce oxygen from hydrogen peroxide in the tumor. Type III photosensitizers aim to work without oxygen by transferring excitation energy directly to biomolecules such as RNA. Photothermal therapy takes another route, converting near-infrared light into heat. High temperatures can rapidly ablate tissue but risk collateral damage; mild heating around 42–45°C may instead improve perfusion, relieve hypoxia and activate NF-κB and STAT1-linked inflammatory programs. The trade-off is that heat-shock proteins can protect tumor cells, prompting efforts to inhibit HSP70 during treatment.

Ultrasound may be particularly useful for tumors buried deep within the body because acoustic energy can penetrate tissue and be focused under imaging guidance. High-intensity focused ultrasound can destroy tumor tissue through heat, releasing tumor antigens and heat-shock proteins that stimulate adaptive immunity. Mechanical forms of focused ultrasound, including histotripsy, use pressure waves and cavitation—the formation and collapse of microscopic bubbles—to fragment tissue while limiting thermal buildup. The resulting release of calreticulin and HMGB1 can push macrophages toward inflammatory activity. Yet the immune effect depends on the amount of tissue disrupted: very small ablation volumes may not provide enough antigenic material to overcome suppression, making combination with immune checkpoint blockade important. Ultrasound-targeted microbubble destruction offers a different mechanism. Cavitating microbubbles temporarily disturb blood-vessel walls and cell membranes, increasing vascular permeability and potentially altering macrophage recruitment. Sonodynamic therapy uses ultrasound to activate sensitizers and generate reactive oxygen species, pairing deep-tissue access with oxidative tumor injury. Its major obstacle remains hypoxia, which has spurred the development of oxygen-generating particles and systems that consume tumor lactate.

Electrical stimulation connects tumor treatment to the electrophysiology of immune cells. Nanosecond pulsed stimulation delivers extremely brief, intense electric pulses that create transient nanopores in cell and organelle membranes. The resulting calcium flux, endoplasmic-reticulum stress and reactive oxygen production can induce immunogenic cell death and activate inflammatory circuits such as cGAS–STING. Preclinical studies described in the review associate this approach with depletion of M2-like macrophages, increased M1-like activity and reductions in regulatory T cells and suppressor cells. Tumor-treating fields use much gentler alternating fields—roughly 1–3 volts per centimeter at 100–300 kilohertz—to disrupt cancer-cell division. Their immune effects appear to arise partly because dying tumor cells release danger signals that activate macrophages through NF-κB and MAPK pathways, although direct in vivo evidence for macrophage reprogramming remains limited. Piezoelectric materials could provide a wireless alternative: ultrasound mechanically deforms a material such as β-phase polyvinylidene fluoride, generating a local electric potential. That signal can open voltage-gated calcium channels and activate a calcium–CAMK2A–NF-κB axis, while some piezoelectric materials also catalyze reactive oxygen species.

Magnetic approaches offer deep penetration without requiring an external beam to pass through the entire tumor. Magnetic nanoparticles can convert an alternating magnetic field into localized heat, a process known as magnetic hyperthermia. Mild heating between about 39 and 45°C may release danger signals from tumor cells while also improving the inflammatory environment. At the same time, acidic tumor conditions or lysosomal processing can release iron ions from particles. Through Fenton and Fenton-like reactions, iron catalyzes the formation of highly reactive hydroxyl radicals, which can damage cancer cells and act as redox signals that favor M1-like macrophage programs. Some particles may influence macrophages without meaningful heating by disturbing iron homeostasis directly, although those effects depend strongly on size, shape, surface chemistry and intracellular dissolution. Radiation adds a clinically established but dose-sensitive option. Moderate doses of roughly 2–10 gray can increase inflammatory macrophage markers through HMGB1, ROS, ATM kinase and NF-κB signaling. Higher doses may worsen hypoxia and activate the HIF-1α–SDF-1–CXCR4 pathway, drawing in immunosuppressive macrophages instead. Ultra-high-dose-rate FLASH radiation has shown a more favorable M1/M2 balance in preclinical work, but the optimal dose, fractionation and treatment sequence remain unresolved.

The review’s central message is not that one form of energy is destined to replace immunotherapy, but that physical stimulation could make immune treatments more precise and more effective. Each modality has a different clinical niche: light is naturally suited to superficial or endoluminal lesions; focused ultrasound can reach deep targets; electrical fields are attractive where electrodes or transducer arrays can be positioned; magnetic systems can act remotely but generally require reliable nanoparticle deposition; and radiotherapy already has established planning and delivery infrastructure. The field is still dominated by laboratory and animal studies, and macrophage polarization is highly dependent on tissue context and stimulation parameters. A treatment that promotes inflammation in one tumor could produce tolerance or immunosuppression in another if the dose, timing, oxygen level or metabolic state is different. Future progress will require standardized energy dosimetry, imaging-guided delivery, spatial and single-cell immune profiling, and careful monitoring of normal-tissue injury. If those hurdles can be overcome, externally controlled energy may offer a powerful way to turn the tumor’s most adaptable immune residents against the cancer they have been helping to protect.