Aggressive features of hepatocellular carcinoma (HCC) are highly related to liver tumor-initiating cells (TICs), which are heterogeneous and plastic. In this issue of Cancer Cell, Yang et al. reveal the ability of CD49f-high TICs in shaping the tumor immunosuppressive microenvironment in HCC.

Seed et al. explore a cohort of PARPi-treated advanced prostate cancers, studying plasma cell-free DNA samples for genomic alterations that provide drug resistance. They find multiple mutations emerging in parallel over time and show links to clinical outcome, and evidence of how tumors with BRCA2 deletions can survive PARPi blockade.

Analysis of 27,810 patients with advanced cancers treated with anti-PD-1/L1 therapies shows that immune gene signatures or immune cell infiltration is not universally associated with mutation burden or long-term survivors after immunotherapies across cancer entities. Thus, immunological stratification of tumors has limited bearing on the immunogenicity of tumors or immunotherapy outcomes.

Seed et al. explore a cohort of PARPi-treated advanced prostate cancers, studying plasma cell-free DNA samples for genomic alterations that provide drug resistance. They find multiple mutations emerging in parallel over time and show links to clinical outcome, and evidence of how tumors with BRCA2 deletions can survive PARPi blockade.

Hänggi et al. investigate how tumor necroptosis regulates anti-tumor immunity and find an unexpected role for interleukin-1α (IL-1α) release by dying cells in promoting tumor growth by driving recruitment and functional alterations of myeloid cells, thereby suppressing T cell effector function at steady-state and during chemotherapy.

Whether cytotoxic T lymphocytes (CTLs) exert protumorigenic effects remains elusive. Huang et al. reveal that macrophages cross-present to clonally expanded CD103+ CTLs in the pericancerous area in hepatocellular carcinoma (HCC). This process activates the NLRP3 inflammasome, inducing macrophage pathogenicity and diminishing the therapeutic efficacy of ICB treatment.

Itaconate is a metabolite produced by macrophages upon infection and acts as an antimicrobial molecule. In this issue of Cancer Cell, Lin et al. found that itaconate produced by tumor-associated macrophages is taken up by cancer cells via the transporter solute carrier family 13 member 3 (SLC13A3), promoting resistance to immune checkpoint inhibitors.