This dataset comprises label-free quantitative DIA proteomics of the human colorectal adenocarcinoma cell line HT-29 under four conditions: untreated control, X-ray irradiation, TFEB knockdown, and TFEB knockdown plus irradiation (n = 3 biological replicates per group). The study investigates how TFEB regulates radiation-induced lysosomal membrane permeabilization (LMP), ER proteostasis and immunogenic cell death. Raw mass spectrometry files (.raw), DIA-NN v1.8.1 search results, the search FASTA database and associated metadata are provided.