Chloride Channels as Determinants of Anti-Cancer Drug Response: Why the Therapeutic Direction Reverses Between Channels and Between Tissues

Background/Objectives: Resistance to cytotoxic chemotherapy and radiotherapy is usually attributed to DNA repair, drug efflux and apoptotic threshold. Chloride channels intersect these processes but are rarely considered as a group. This review asks whether chloride flux forms a coherent, targetable axis of treatment response and, if not, how the therapeutic direction differs by channel and tissue. Methods: PubMed was searched to 23 August 2026; all free-text searches were re-executed on 22 September 2026 and supplemented by controlled-vocabulary searches. Cited records were checked against NCBI E-utilities and screened for retractions. Claims were graded by whether pharmacological phenotypes were reproduced by genetic perturbation and by the available target-engagement and replication evidence. Results: The therapeutic direction is not uniform. In experimental models, LRRC8A- and LRRC8D-containing channels mediate substantial platinum uptake, and dose-stratified associations between their expression and outcome have been reported in head and neck cancer, supporting prospective evaluation as predictive biomarkers; contrary reports in ovarian, colon and breast models indicate that this direction is established for platinum uptake rather than for cytotoxic resistance in general. CFTR is an intestinal tumour suppressor and the only channel reviewed with an approved potentiator, yet its direction reverses in glioma, with a prostate report of CFTR-dependent cisplatin resistance pointing in the same direction. Conversely, ClC-3, ANO1 and CLIC1 are associated with resistance when gained, although CLIC1 is better supported as a determinant of drug response than of tumorigenesis. Sixteen modulators are compared by potency, assay format, selectivity/counter-screening and clinical status; widely used blockers are often poorly selective. Conclusions: Chloride transport is not a single therapeutic target class. Candidate chloride-channel blockers should be counter-screened against LRRC8/VRAC before combination with platinum therapy, and CFTR potentiation should not be generalised across tumour types. Conflicting evidence is reported alongside the directions it qualifies rather than set aside.