Current advancements in the investigation of mitochondria-targeting organic sensitizers in cancer immunotherapy

Abstract

Cancer immunotherapy has transformed oncological treatment paradigms, yet tumor resistance and immune evasion continue to limit therapeutic efficacy. Mitochondria-targeting organic sensitizers (MTOSs) represent an emerging class of therapeutic agents that exploit mitochondrial dysfunction as a convergent node for tumor elimination and immune activation. As central regulators of cellular metabolism, apoptotic signaling, and immune cell function, mitochondria serve as critical determinants of tumor progression and the immunological landscape within the tumor microenvironment (TME). This comprehensive review synthesizes the latest advances (2023–2025) in MTOS-mediated cancer immunotherapy, systematically examining the capacity of MTOSs to induce diverse forms of regulated cell death and orchestrate antitumor immune responses. MTOSs demonstrate remarkable versatility in triggering mitochondria-dependent apoptosis, immunogenic cell death (ICD), necroptosis, pyroptosis, ferroptosis, and autophagic cell death through strategic disruption of mitochondrial homeostasis. These sensitizers modulate key mitochondrial functions including membrane potential dynamics, reactive oxygen species (ROS) generation, electron transport chain integrity, and calcium homeostasis, thereby releasing damage-associated molecular patterns (DAMPs) that potently activate both innate and adaptive immunity. Current MTOS platforms encompass small-molecule sensitizers, polymeric nanocarriers, metal–organic complexes, and biomimetic systems, each offering distinct advantages in mitochondrial targeting and therapeutic efficacy. Clinical translation faces significant challenges including variable mitochondrial targeting efficiency due to transmembrane transport limitations and TME pH fluctuations, systemic toxicity risks from nonspecific metal ion release in metal–organic complexes, insufficient long-term biocompatibility evaluation, and the predominant reliance on simplified tumor models that inadequately reflect clinical heterogeneity and complex spatiotemporal dynamics of mitochondrial damage-immune remodeling interactions. Future research directions emphasize the multidisciplinary integration of synthetic biology, nanotechnology, and computational approaches to engineer next-generation intelligent sensitizer platforms with enhanced TME-adaptive capabilities, enabling precise mitochondrial intervention and immune modulation for improved cancer immunotherapy outcomes.