CD8 ⁺ tumor-infiltrating lymphocytes (TILs) are associated with improved survival in triple-negative breast cancer (TNBC) yet have no association with survival in estrogen receptor–positive (ER ⁺ ) BC. The basis for these contrasting findings remains elusive. We identified subsets of BC tumors infiltrated by CD8 ⁺ T cells with characteristic features of exhausted T cells (T _EX ). Tumors with abundant CD8 ⁺ T _EX exhibited a distinct tumor microenvironment marked by amplified interferon-γ signaling–related pathways and higher programmed death ligand 1 expression. Paradoxically, higher levels of tumor-infiltrating CD8 ⁺ T _EX associated with decreased overall survival of patients with ER ⁺ BC but not patients with TNBC. Moreover, high tumor expression of a CD8 ⁺ T _EX signature identified dramatically reduced survival in premenopausal, but not postmenopausal, patients with ER ⁺ BC. Finally, we demonstrated the value of a tumor T _EX signature score in identifying high-risk premenopausal ER ⁺ BC patients among those with intermediate Oncotype DX Breast Recurrence Scores. Our data highlight the complex relationship between CD8 ⁺ TILs, interferon-γ signaling, and ER status in BC patient survival. This work identifies tumor-infiltrating CD8 ⁺ T _EX as a key feature of reduced survival outcomes in premenopausal patients with early-stage ER ⁺ BC.

Gastrointestinal cancers are a leading cause of cancer morbidity and mortality worldwide with 4.2 million new cases and 3.2 million deaths estimated in 2020. Despite the advances in primary and adjuvant therapies, patients still develop distant metastases and require novel therapies. Mitogen‑activated protein kinase (MAPK) cascades are crucial signaling pathways that regulate many cellular processes, including proliferation, differentiation, apoptosis, stress responses and cancer development. p38 Mitogen Activated Protein Kinases (p38 MAPKs) includes four isoforms: p38α (MAPK14), p38β (MAPK11), p38γ (MAPK12), and p38δ (MAPK13). p38 MAPK was first identified as a stress response protein kinase that phosphorylates different transcriptional factors. Dysregulation of p38 pathways, in particular p38γ, are associated with cancer development, metastasis, autophagy and tumor microenvironment. In this article, we provide an overview of p38 and p38γ with respect to gastrointestinal cancers. Furthermore, targeting p38γ is also discussed as a potential therapy for gastrointestinal cancers.