Poor responses to BCG immunotherapy remain a challenge for successful treatment of NMIBC. The authors report sex differential responses of B cells to carcinogenic stimuli and BCG in bladder cancer, suggesting new approaches to immunotherapy for NMIBC.

Immunotherapy has limited efficacy in GBM. The authors develop and use a machine learning approach to identify cell fate determinants that force GBM cells to acquire DC-like functions, establishing an immunotherapy that is effective in GBM models.

Tumor-antigen heterogeneity limits CAR T-cell efficacy against solid tumors. The authors overcome this by developing CAR T cells that overexpress LIGHT, which provides an antigen-independent mechanism of CAR-mediated cytolysis while simultaneously providing costimulatory properties to the T cells.

The sialic acid/Siglec-9 pathway is shown to be inhibitory for human T cells. Siglec-9–based chimeric switch receptors enhance the antitumor activity of T-cell receptor–engineered T cells in vitro and in vivo, suggesting ways to improve cell-based immunotherapy.

Despite having several positive immunomodulatory effects, MEKis also suppress T-cell function. The authors show this suppression can be mitigated by combining an intermittent MEKi regimen with GITR costimulation for an improved antitumor effect with CTLA-4 checkpoint blockade.

The authors show that an RNA-encoded mouse serum albumin–IL2 fusion protein has improved pharmacokinetics compared with wild-type IL2 and potentiates RNA vaccine–induced T-cell responses and antitumor activity. These data support clinical development of this approach.

The authors show that NKR signals enhance TCR signaling in human T lymphocytes, allowing them to selectively recognize low levels of tumor-associated antigens on “distressed” cancer cells, providing tools to develop novel immunotherapies with enhanced potency and selectivity.

This study reveals that FBXO38 enhances NK cell–mediated antitumor immunity by maintaining IL15 signal strength. FBXO38 overexpressed human NK cells exert greater therapeutic efficacy in xenograft mouse models.

Low cancer-cell MR1 expression could limit the therapeutic potential of MR1-restricted T cells (MR1T cells). The authors show that ERK1/2 regulate MR1 expression and ERK1/2 inhibition increases MR1 protein expression, promoting cancer-cell recognition and killing by MR1T cells.

The authors report a mechanism by which hypoxic HNSCC cells evade the immune system, showing that they downregulate MHC-I through intracellular or externalized HIF1A-AS2. HIF1A-AS2 is a long noncoding RNA that acts as a scaffold to increase autophagic degradation of MHC-I.