Two studies revealed tumor‑intrinsic mechanisms that blunt immune checkpoint efficacy. Zhao et al. (Cell Research, 2026) reported that tumor PD‑L1 can trigger beta‑2 microglobulin (β2m) degradation to escape cytotoxic T lymphocyte killing, identifying a previously unrecognized intrinsic resistance pathway. The work provides molecular detail on PD‑L1 beyond its canonical extracellular immune‑checkpoint role. A separate study described a TP53‑LGALS4 axis that modulates the colorectal tumor microenvironment and enhances anti‑PD‑L1 therapy efficacy in preclinical models, pointing to potential combination targets. Together these papers propose biomarker strategies and candidate co‑therapies to overcome checkpoint resistance and guide trial design.