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Significance The work provides a conceptual advance in functionally defining the cross talk of tumor epithelia with cancer-associated fibroblastic cells contributing to tumor progression and therapeutic resistance. Independent of protein-based signaling molecules, prostate cancer cells secreted mitochondrial DNA to induce associated fibroblasts to generate anaphylatoxin C3a to support tumor progression in a positive feedback loop. Interestingly, the standard of care chemotherapy, docetaxel, used to treat castrate-resistant prostate cancer was found to further potentiate this paracrine-signaling axis to mediate therapeutic resistance. Blocking anaphylatoxin C3a signaling cooperatively sensitized prostate cancer tumors to docetaxel. We reveal that docetaxel resistance is not a cancer cell-autonomous phenomena and that targeting an immune modulator derived from cancer-associated fibroblasts can limit the expansion of docetaxel-resistant tumors.

Cancer epithelia-derived mitochondrial DNA is a targetable initiator of a paracrine signaling loop that confers taxane resistance