Background/Objectives: Melanoma is the deadliest form of skin cancer. Resistance to alkylating agents such as Temozolomide (TMZ) and Dacarbazine (DTIC) limits their clinical benefit, as these drugs remain palliative options when immunotherapies and targeted treatments fail. CSA/ERCC8 is a key component of transcription-coupled nucleotide excision repair (TC-NER), a pathway responsible for removing UV-induced DNA lesions. In principle, loss of a DNA repair factor would be expected to increase carcinogenesis. However, although CSA loss-of-function causes Cockayne Syndrome (CS), affected patients do not exhibit increased skin cancer incidence, suggesting that CSA impairment promotes apoptosis rather than tumor development. This paradox raises the possibility that CSA inhibition may selectively target melanoma cell survival pathways. Methods: The expression of CSA/ERCC8 was analyzed by qRT-PCR and Western blot. ERCC8 was silenced using antisense oligonucleotides. Cell viability, apoptosis, cell cycle progression, drug sensitivity, and DNA damage were assessed by functional assays, including IC50 determination and Bliss analysis for drug interactions. Results: We identified CSA/ERCC8 as a driver of melanoma chemoresistance. CSA was markedly overexpressed in primary and metastatic melanoma cells. ERCC8 silencing reduced proliferation, induced apoptosis, and significantly enhanced sensitivity to low doses of TMZ and DTIC while sparing normal cells. Conclusions: CSA represents a promising therapeutic target to overcome chemoresistance in melanoma. Its inhibition enhances the efficacy and selectivity of alkylating agents, supporting its potential as a salvage strategy for refractory disease and warranting further preclinical and clinical investigation.

Melanoma is the deadliest form of skin cancer, with resistance to alkylating agents such as Temozolomide (TMZ) and Dacarbazine (DTIC) further limiting the efficacy of these drugs, which remain palliative options when modern immunotherapies and targeted therapies fail. Here, we identify the Cockayne Syndrome group A (CSA) protein—a key component of Transcription-Coupled Nucleotide Excision Repair (TC-NER)—as a novel driver of melanoma chemo-resistance. CSA is markedly over-expressed in both primary and metastatic melanoma cells. Silencing CSA using Antisense Oligonucleotides (ASOs) robustly reduces melanoma cell proliferation, induces apoptosis, and—critically—sensitizes cells to low doses of TMZ and DTIC, while sparing normal cells. Notably, although CSA loss-of-function underlies Cockayne Syndrome (CS), a disorder characterized by defective repair of UV-induced DNA damage, these patients do not exhibit an increased incidence of skin cancer. This paradox highlights a unique biological context in which impaired CSA function promotes cellular apoptosis rather than carcinogenesis, suggesting that CSA inhibition could selectively cripple melanoma cells. These findings establish CSA as a promising therapeutic target to overcome chemo-resistance in melanoma. Combining CSA inhibition with alkylating agents offers a potential salvage strategy in patients with refractory disease and warrants further preclinical and clinical investigation.