Molecularly Engineered Nanoagents with Efficient Free Radicals Generation and Photothermal Conversion Performance for Enhanced Tumor Photoimmunotherapy via Targeting Lactate Metabolism‐Immune Circuit Rewiring

Abstract Photodynamic therapy (PDT) and photothermal therapy (PTT) have emerged as promising modalities against tumor growth and distant metastases via inducing apoptosis and immunogenic cell death (ICD). However, their therapeutic efficacy is profoundly compromised by the acidic tumor microenvironment fueled by lactate extrusion, orchestrating multifaceted immunosuppression. Herein, a lactate metabolism checkpoint blockade strategy targeting monocarboxylate transporter 4 (MCT4) is proposed to augment photoimmunotherapy by co‐delivering MCT4 inhibitor syrosingopine (SY) and a phototheranostic agent L8BO (L8). Boasting robust intramolecular charge transfer (ICT) characteristics and an extended π‐conjugated architecture with lengthy alkyl chains, L8 possesses a diminished singlet‐triplet energy gap (∆ S‐T ) alongside elevated light‐harvesting property, achieving exceptional free radicals generation and 46.2% photothermal conversion efficiency (PCE). Triggered by lactate sequestration‐induced intracellular acidification, L8@SY nanoparticles (NPs)‐enabled photoimmunotherapy potently activates dendritic cells (DCs) maturation while eliciting substantial infiltration of T lymphocytes. Concurrently, natural killer (NK) cell activation and memory T‐cell differentiation are achieved, thereby suppressing both localized and distal tumor progression whilst concomitantly curtailing pulmonary metastatic dissemination. In brief, this study provides a novel combinatorial paradigm to potentiate photoimmunotherapy by targeting the lactate metabolism‐immune circuit rewiring strategy.