Integrating siRNA targeting PKM2 with photodynamic therapy to induce tumor energy collapse

Abstract

Tumor cells exhibit an exceptionally high demand for energy to sustain uncontrolled proliferation and predominantly rely on glycolysis, rendering them vulnerable to energy-targeting interventions. However, metabolic plasticity often enables adaptive compensation, thereby limiting the efficacy of conventional metabolic starvation strategies. Herein, we present a synergistic therapeutic strategy that integrates siRNA targeting pyruvate kinase M2 (PKM2) with photodynamic therapy (PDT) to induce tumor energy collapse. A cationic polymer–chlorin e6 (Ce6) nanocomplex was constructed by conjugating Ce6 to fourth-generation polyamidoamine (PAMAM), enabling efficient encapsulation and intracellular delivery of PKM2-specific siRNA (siPKM2/CPN). siRNA targeting PKM2 effectively suppressed glycolytic flux, reduced ATP production, and impaired mitochondrial oxidative phosphorylation, thereby inducing severe energy deprivation in tumor cells. Notably, PKM2 knockdown sensitized tumor cells to PDT by amplifying reactive oxygen species generation and exacerbating mitochondrial dysfunction. Mechanistically, the combined treatment activated the mitochondrial apoptotic pathway, as evidenced by increased mitochondrial membrane permeabilization, cytochrome c (Cyt c) release, and caspase-3 activation, ultimately leading to enhanced tumor cell apoptosis. This dual-targeting strategy effectively overcomes tumor metabolic adaptability and highlights metabolic modulation as a promising approach for the next-generation combination cancer therapy.