Background <p>Chromatin regulators (CRs) play a critical role in tumorigenesis, drug response, and prognosis, with dysregulation of chromatin regulator genes (CRGs) potentially disrupting the tumor immune microenvironment (TME) and influencing immune responses in cervical cancer. However, the prognostic and therapeutic implications of integrating CRGs and TME parameters in cervical cancer remain poorly understood.</p> Methods <p>This study used prognostic CRGs and TME cell signatures identified through Cox regression and Kaplan–Meier survival analyses to construct the CRG and TME score. The CRG score for each cell was calculated by integrating single-cell and spatial transcriptome, which were subsequently integrated to develop a CRG-TME classifier for prognostic prediction. The prognosis, somatic mutations, immune characteristics, therapeutic benefits, and drug sensitivity were then analyzed across CRG-TME defined subgroups.</p> Results <p>Both CRG score and TME score demonstrated prognostic value, and the high CRG score group showed distinct alterations in TME signaling dynamics and increased intensity of intercellular communication. Patients in CRG^low/TME^high subgroup exhibited enhanced prognosis and therapeutic responses compared to other subgroups, attributable to variations in tumor somatic mutations, immune-related molecules, cancer signaling pathways and drug sensitivity. Additionally, the clinical sample verification and in vitro experiments demonstrated that the key prognostic gene TSPYL2 was downregulated in cervical cancer tissues and overexpression of TSPYL2 inhibited the malignant progression of cervical cancer cells via regulating MAPK pathway and immune escape.</p> Conclusions <p>This study develops a novel CRG-TME classifier to predict prognosis and therapy response in cervical cancer and unveils the inhibitory effect and underlying mechanism of TSPYL2 on cervical cancer progression.</p>