Marine sponges are predicted to be winners in the future ocean due to their exemplary adaptive capacity. However, while many sponge groups exhibit tolerance to a wide range of environmental insults, calcifying sponges may be more susceptible to thermo-acidic stress. To describe the gene regulatory networks that govern the stress response of a calcareous sponge, Leucetta chagosensis (class Calcarea, order Clathrinida), individuals were subjected to warming and acidification conditions based on the climate models for 2100. Transcriptome analysis and gene co-expression network reconstruction revealed that the unfolded protein response (UPR) was activated under thermo-acidic stress. Among the upregulated genes were two lineage-specific homologs of X-box binding protein 1 (XBP1), a transcription factor that activates the UPR. Alternative dimerization between these XBP1 gene products suggests a clathrinid-specific mechanism to reversibly sequester the transcription factor into an inactive form, enabling the rapid regulation of pathways linked to the UPR in clathrinid calcareous sponges. Our findings support the idea that transcription factor duplication events may refine evolutionarily conserved molecular pathways and contribute to ecological success.