Background: The tumor suppressor gene STK11 encodes LKB1 kinase that is a key regulator for cell metabolism, and TP53 gene encoding p53, a transcription factor known as the “Guardian of the genome”, critically protects the DNA integrity of the cell. STK11/TP53-deficient cancers are vulnerable to metabolic stress, redox stress, etc. and resistant to most therapies including immunotherapy, but there is no therapy so far that can specifically target this population of cancer patients. Notably, somatic mutations in KRAS, TP53 etc. are the major drivers, while germline mutations in STK11 and TP53 are the major inherited risk factors for pancreatic cancer that has no efficacious therapies yet. Methods: The IC50s of our first-in-class PDIA6/IRE1 modulator NAI003, singly or in combination with a variety of marketed anticancer drugs, against multiple cancer cell lines and patient-derived primary cancer cells, were determined by CCK-8 cell viability assay or CellTiter-Glo® luminescent cell viability assay. Results: NAI003 series compounds selectively kill or inhibit the proliferation of 20 out of 170 human cancer cell lines (with at least one compound having IC50 < 10 μM) via regulated cell death, 11 and 16 out of the 20 cells harbor STK11 and TP53 genetic and functional defects, respectively, and 8 out of the 20 cells carry defects of both genes. Further, NAI003 series compounds, particularly NAI003-7 (that dually targets PDIA6/IRE1 and HDACs), potently kill patient-derived primary cancer cells harboring STK11/TP53 genetic and functional defects. For patient-derived primary pancreatic cancer cells in vitro, NAI003-7 outperformed the current standard of care (SOC) therapy. In contrast, up to a concentration of 50 μM, NAI003 compounds exhibit no cytotoxicity to normal human cells (PBMCs, Jurkat T cells, HCerEpiC cells, etc.), consistent with their good in vivo safety profiles. Their in vivo efficacies in PDX models are currently under investigation. Conclusion: PDIA6/IRE1-regulated ER stress is a target of vulnerability in STK11/TP53-deficient cancers, and NAI003 is a potential first-in-class small-molecule ER stress modulator that can specifically treat cancer patients harboring STK11/TP53 genetic and functional defects. This compound holds great promise in tackling hard-to-treat cancers such as pancreatic cancer, and in overcoming cancer drug resistance by various mechanisms.