Unconventional T cells, including invariant natural killer T (iNKT) cells, gamma delta (γδ) T cells, and mucosal-associated invariant T (MAIT) cells, play important roles in both innate and adaptive immunity. These cells respond to tumors rapidly and influence the tumor microenvironment (TME). Recent advances in understanding their biology, as well as the development of novel therapeutic approaches, have underscored their potential in cancer immunotherapy. This commentary will assess these advances and translational possibilities in the field.

(Cancer Cell 38, 212–228; August 10, 2020)

Although immunity is an important component of cancer therapy responses, suppressive immune feedback restricting anti-tumor activity has not been extensively examined. In this issue of Cancer Cell, Lamorte et al. identify expression of the cytokine IL-33 by lymph node macrophages after therapy as an important inhibitor of therapeutic efficacy. Notably, antagonizing IL-33 function significantly increases therapeutic responses to chemo- and targeted-therapy revealing IL-33 responses as an actionable target to augment anti-tumor immunity when chemotherapy or other therapeutic modalities are employed.

Yang et al. report that HIF-1α acts as a main driver of tumor resistance to cuproptosis under hypoxia. Mechanistically, they reveal that HIF-1α can repress DLAT expression and promote MT2A to sequester mitochondrial copper. HIF-1α inhibition increases the susceptibility of cancer to cuproptosis in in vivo preclinical models.

The analysis of fragmentation patterns in plasma DNA (i.e., fragmentomics) is actively explored. Lam et al. reveal that integrating fragmentomics and quantitative analysis of plasma Epstein-Barr virus DNA significantly improves the prediction of future nasopharyngeal carcinoma risk. This suggests the potential of fragmentomics-based risk prediction for other types of cancer.

In this issue of Cancer Cell, Acha-Sagredo et al. reveal an interferon-high immunophenotype in colorectal cancer that predicts responsiveness to immune checkpoint inhibitors across both mismatch repair-deficient and mismatch repair-proficient subtypes. They identify CD74 as a biomarker and establish the importance of epithelial interferon levels in regulating immune responses.

Denkert et al. evaluate adaptation of luminal high-risk breast cancer to neoadjuvant therapy in longitudinal biopsies from Penelope-B trial and identify five adaptive subtypes (AC1-5) by comparing pre- and post-therapeutic paired tumor samples, supporting an extended molecular classification of breast cancer patients for the identification of high-risk populations.

Braun et al. demonstrate that local adiponectin induced by extracorporeal photopheresis (ECP) reduces pro-inflammatory T and myeloid cells numbers in colitis tissue after immune checkpoint inhibition in mice and patients. The phagocytic uptake of apoptotic cells in inflamed tissues polarizes intestinal macrophages toward a tolerogenic phenotype and induces adiponectin production.

Schiantarelli et al. compare genomic profiles from tumor biopsies of melanoma patients who exhibit heterogeneous responses to immune checkpoint inhibitors. Three patients had resistance-associated mutations in SEC24C/D. SEC24 mutations exhibit diminished STING signaling, antigen presentation, and lower T cell activation. They nominate aberrant STING trafficking in acquired resistance to ICIs.