Abstract

PDA-ICG@PEI/siPKM2 integrates photothermal ablation, ICD, and PKM2 silencing. • PDA stabilizes ICG and boosts photothermal efficacy. • siPKM2 depletes ATP, impairing HSP70 thermotolerance. • Synergy of phototherapy-triggered ICD and gene therapy enables durable tumor control. Cancer treatment continues to face challenges due to tumor heterogeneity, metastasis, and adaptive resistance. Phototherapy represents a promising non‑invasive approach that can achieve localized tumor ablation and systemic immune activation through immunogenic cell death (ICD). However, its efficacy is hindered by the instability of photoactive agents such as indocyanine green (ICG) and by therapy‑induced resistance, particularly heat shock protein 70 (HSP70)‑mediated thermotolerance. To address these limitations, an integrated nanotherapeutic platform was developed based on polydopamine (PDA) co‑loaded with ICG and siRNA targeting pyruvate kinase M2 (siPKM2), and functionalized with polyethylenimine (PEI). The resulting PDA‑ICG@PEI/siPKM2 nanoplatform executes three functionally coordinated stages: (1) enhanced photothermal ablation for immediate tumor destruction, which triggers robust ICD; (2) ICD‑driven activation of systemic antitumor immunity; and (3) siPKM2‑mediated dual modulation of tumor metabolism and signaling—depleting glycolytic ATP to impair HSP70‑mediated thermotolerance while suppressing oncogenic pathways. Together, these mechanisms create a self‑reinforcing cycle in which phototherapy‑induced ICD primes an immune response that is further amplified and sustained by PKM2‑targeted gene therapy. This combinatory strategy synergistically enhances phototherapeutic efficacy and immune activation, offering a promising approach for tumor control.