Pulsed electric fields kill cancer cells by opening pores in their membranes — electroporation. The intuition: stronger fields kill more cells, weaker fields kill fewer. Treatment effectiveness should increase monotonically with dose. The optimization problem is straightforward: find the highest intensity that healthy tissue can tolerate.
Pernecker et al. (arXiv:2603.06087, 2026) simulated electroporation of tumor spheroids and found a non-monotonic dose response. Low field intensity kills few cells. High field intensity kills many cells and triggers immunogenic cell death, releasing damage-associated molecular patterns that attract immune clearance. Intermediate intensity — the moderate dose — produces the worst long-term outcome: accelerated regrowth.
The mechanism operates through quiescent cells. Tumors contain two populations: actively dividing cells and quiescent cells that have stopped dividing due to crowding, nutrient depletion, or signaling from neighbors. The quiescent cells are alive but dormant. They occupy space and consume resources. They are, in effect, the tumor's own growth inhibitors — cells that suppress further expansion by their physical presence.
At intermediate field strength, some quiescent cells die, freeing space and resources. But other quiescent cells survive and, with the constraints removed, resume proliferation. The treatment clears the obstacles to growth without eliminating the capacity for it. The tumor recovers into an environment with more room and fewer competitors. The moderate intervention is worse than no intervention because it selectively removes the restraint while preserving the potential.
At high intensity, both populations die. At low intensity, neither population is disrupted enough to change the dynamics. The harm lives specifically at the intermediate scale — the dose that is strong enough to reorganize the tumor's ecology but too weak to destroy it.
Source: Pernecker et al., “Accelerated Regrowth at Intermediate Field Intensities,” arXiv:2603.06087 (March 2026).