| Rank |
Pathway / Axis |
Cancer / Tumor Context |
Normal Tissue Context |
TSF |
Primary Effect |
Notes / Interpretation |
| 1 |
ROS burst (sonosensitizer activation) |
ROS ↑↑ (local); oxidative damage ↑ |
Collateral ROS possible depending on targeting |
P |
Primary cytotoxic driver |
Core SDT mechanism: ultrasound-activated sensitizers generate ROS; effectiveness depends on oxygenation and sensitizer localization. |
| 2 |
Mitochondrial dysfunction (ΔΨm loss) → intrinsic apoptosis |
ΔΨm ↓; cyt-c ↑; caspase-9/3 ↑ (reported) |
↔ / injury possible at high exposures |
R, G |
Apoptosis execution |
Often downstream of ROS; magnitude depends on dose and cell redox fragility. |
| 3 |
Lipid peroxidation / membrane damage |
Membrane integrity ↓; lipid peroxidation ↑ |
Off-target membrane injury possible |
P, R |
Cell damage / necrotic pressure |
ROS and mechanical effects can destabilize membranes; can contribute to necrosis-like death if severe. |
| 4 |
ER stress / UPR activation |
ER stress ↑; CHOP ↑; UPR ↑ (reported) |
↔ / stress response possible |
R, G |
Stress overload |
ROS-triggered protein misfolding and calcium dysregulation can drive UPR and pro-death signaling. |
| 5 |
DNA damage response (DDR) |
DNA oxidation / breaks ↑; γH2AX ↑ (reported) |
↔ / injury possible |
R, G |
Replication stress / apoptosis support |
DNA damage is typically secondary to ROS; relevance depends on tumor proliferation state. |
| 6 |
Ferroptosis-like signaling (context-dependent) |
Lipid ROS ↑; GPX4 pressure ↑ (reported in some SDT papers) |
↔ |
R, G |
Non-apoptotic oxidative death |
Some SDT systems push lipid peroxidation strongly enough to resemble ferroptosis; not universal. |
| 7 |
Autophagy response |
Autophagy ↑ (adaptive) or contributes to death (context) |
↔ |
G |
Stress adaptation |
Autophagy can be protective or pro-death depending on magnitude of SDT stress and sensitizer localization. |
| 8 |
Microenvironment effects (vascular permeability / perfusion) |
Local perfusion changes; permeability ↑ (reported) |
Potential local vascular injury |
P, R |
Delivery modulation |
Ultrasound can increase permeability (esp. with microbubbles); may enhance drug delivery in some protocols. |
| 9 |
Immune activation (DAMPs / ICD-like signals) |
Immunogenic cell death signals ↑ (reported) |
— |
G |
Anti-tumor immunity support |
Cell stress/death can release DAMPs and promote antigen presentation; data vary by model and sensitizer. |
| 10 |
Parameter dependence / safety constraints |
Effect varies with sensitizer + ultrasound settings + oxygenation |
Heating / cavitation injury risk if misapplied |
— |
Translation constraint |
SDT outcomes depend heavily on ultrasound frequency/intensity/duty cycle and sensitizer biodistribution; not “plug-and-play.” |
| Sensitizer Class |
Examples |
Primary Mechanistic Bias |
Dominant Death Pathways (Reported) |
Notes / Interpretation |
| Porphyrins / Hematoporphyrin derivatives |
Hematoporphyrin, Protoporphyrin IX, Photofrin-like agents |
ROS generation (Type I/II-like chemistry under ultrasound) |
Intrinsic apoptosis (ΔΨm ↓, cyt-c ↑), caspases ↑ |
Most classical SDT sensitizers; strong mitochondrial localization; mechanistically closest to PDT analogs. |
| Chlorins / Phthalocyanines |
Chlorin e6 (Ce6), phthalocyanine derivatives |
High ROS yield |
Apoptosis ↑; lipid peroxidation ↑; ER stress ↑ |
Often used in nanoformulations to improve tumor accumulation and ultrasound activation efficiency. |
| Xanthene dyes |
Eosin Y, Rose Bengal |
ROS burst + membrane effects |
Apoptosis ↑; necrotic pressure (dose-dependent) |
Some studies show strong oxidative burst; selectivity depends on uptake and targeting. |
| Repurposed chemotherapeutics |
Doxorubicin, 5-ALA (via PpIX accumulation) |
Combined ROS + intrinsic drug mechanism |
Apoptosis ↑; DDR ↑ |
Dual-mechanism systems: drug effect plus ultrasound-enhanced ROS; schedule-dependent outcomes. |
| Metal-based nanoparticles |
TiO2, ZnO, MnO2-based systems |
ROS catalysis; Fenton-like chemistry |
Lipid peroxidation ↑; ferroptosis-like signaling (reported) |
Often engineered to amplify ROS via catalytic surfaces; ferroptosis signatures reported in some platforms. |
| Organic nano-sonosensitizers |
Polymeric micelles, liposome-loaded sensitizers |
Targeted ROS release |
Apoptosis ↑; immune activation (DAMPs ↑) |
Improved tumor delivery; often combined with immune checkpoint therapy in preclinical systems. |
| Gas-generating / microbubble-assisted systems |
O2-loaded microbubbles, perfluorocarbon systems |
Cavitation + oxygenation enhancement |
Enhanced ROS; vascular disruption |
Used to overcome hypoxia and improve ROS yield; parameter-sensitive. |
| Natural compound–based sensitizers (experimental) |
Curcumin, certain flavins (reported) |
ROS generation (lower potency vs porphyrins) |
Apoptosis ↑ (reported) |
Less standardized; ROS yield and ultrasound responsiveness vary widely. |