Abstract: Mitochondrial double-stranded RNA (mt-dsRNA) can act as an immune signal; however, its effects in cancer depend on where it is generated, buffered, released, and sensed. Herein, we synthesize evidence for four linked checkpoints: duplex formation and modification, intramitochondrial degradation, membrane escape, and receptor-specific decoding. It is found that human-cell and trafficking studies demonstrate that mitochondrial RNA surveillance constrains mt-dsRNA and that a fraction can reach the cytosol. Cancer studies report distinct outcomes: altered mitochondrial RNA turnover can affect acute myeloid leukemia cell state, tumor-derived mt-dsRNA can remodel B-cell leukemia stroma, and pancreatic cancer-associated sensing supports growth. However, these findings do not establish a pan-cancer dependency; we propose that source, compartment, sensor, recipient cell, and signal duration must be resolved before therapeutic direction is assigned. In addition, we outline assays and biomarkers that distinguish an acute antitumor response from chronic inflammation, tumor-supportive signaling, or normal-tissue toxicity. This framework also guides biomarker selection and treatment scheduling, while the clinical benefit remains to be validated.

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