Harnessing HSPB1-targeted radiotheranostics for early diagnosis and precision therapy in colorectal cancer

Colorectal cancer (CRC) has high global incidence and mortality, yet effective diagnostic tools for detecting the adenoma to adenocarcinoma transition are lacking, making identification of adenomas with malignant transformation potential essential for early diagnosis and intervention. This study aimed to identify key biomarkers involved in the adenoma-carcinoma sequence. Based on this discovery, we developed an integrated radionuclide probe for diagnosis and therapy. Through a combination of retrospective clinical analysis, proteomics, and cellular experiments, we identified a significant upregulation of heat shock protein beta-1 (HSPB1) during the adenoma–carcinoma transition, which is closely associated with tumor proliferation, invasiveness, and metastatic potential. Based on this finding, we constructed HSPB1-targeted radiolabeled probes—¹⁷⁷Lu-DPTP. In vitro and in vivo, including early CRC patient-derived xenograft (PDX) and low rectal cancer models, ¹⁷⁷Lu-DPTP demonstrates high targeting specificity and favorable pharmacokinetics, selectively accumulates in HSPB1-high tumors, and produces effective imaging and therapeutic outcomes. It enabled non-invasive diagnosis via molecular imaging while significantly inhibiting tumor growth through targeted radiotherapy, without notable toxicity. In conclusion, our study highlights the pivotal role of HSPB1 in colorectal adenoma–carcinoma progression and demonstrates the potential of HSPB1-targeted probes for early diagnosis and precision therapy of CRC, offering a promising strategy for improved screening and treatment outcomes.