Houston Methodist-led research identified a signaling pathway that may drive intrinsic resistance to trastuzumab deruxtecan in metastatic breast cancer. Published in Clinical Cancer Research, the study points to S100–RAGE signaling as a potential driver of resistance and suggests pathway blockade could restore tumor sensitivity. In parallel, Mayo Clinic researchers reported an immune “off switch” exploited by cancer cells and pathogens to weaken T-cell responses, described in the Journal of Clinical Investigation. The findings center on a TRAILshort protein variant and provide mechanistic framing for why immune defenses fail across cancers and infectious or inflammatory conditions. Both studies underscore how resistance and immune evasion are increasingly mapped to specific molecular axes—creating clearer targets for combination regimens and biomarker development rather than broad immunotherapy intensification alone.