Stress-resolved longitudinal single-cell and spatial transcriptomic analysis supports a tumor–immune remodeling framework during chemoradiotherapy in cervical cancer

Abstract

Concurrent chemoradiotherapy (CRT) is standard for locally advanced cervical cancer, but early links between tumor adaptation and immune dysfunction remain incompletely resolved. We conducted an exploratory secondary analysis of public longitudinal single-cell RNA-sequencing data from paired cervical cancer samples collected before and during chemoradiotherapy (CRT), together with progression-oriented external single-cell cohorts and spatial transcriptomic sections. Tumor programs were decomposed into adaptive resistant-like, pan-stress, and niche-sculpting components. Associations with CD8 T-cell states were evaluated using patient-aware summaries, prespecified stress adjustment, and exploratory relay-aware models used only for candidate prioritization. Early CRT-associated remodeling was most pronounced in the T-cell/natural killer (T/NK) compartment, whereas epithelial change was better captured by state redistribution. Across 16 patient–timepoint summaries, the niche-sculpting program had the largest positive point-estimate association with the CD8 senescence-like fraction among the three tumor programs. In 13 eligible summaries, its association with the senescence-like CD8-state score remained positive after prespecified stress adjustment but did not reach conventional statistical significance. In 12 complete-case observations from 8 patients, patient-grouped Ridge and Lasso analyses preferentially retained the terminal myeloid/CD8 composite, but bootstrap uncertainty and non-identifiable ordering precluded mechanistic interpretation. The n = 3 paired-delta analysis was descriptive. External cohorts showed context-dependent and partly discordant cross-sectional patterns rather than matched validation, while spatial analyses provided descriptive localization only. These findings support a stress-resolved, evidence-graded framework for treatment-associated tumor-immune remodeling during cervical cancer CRT and nominate tumor-myeloid-CD8 associations for functional testing. The results are hypothesis-generating and require perturbational and prospective validation.