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Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan‐cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis‐defined CNA signatures are predictive of glycolytic phenotypes, including 18 F‐fluorodeoxy‐glucose (FDG) avidity of patient tumors, and increased proliferation. The primary CNA signature is enriched for p53 mutations and is associated with glycolysis through coordinate amplification of glycolytic genes and other cancer‐linked metabolic enzymes. A pan‐cancer and cross‐species comparison of CNAs highlighted 26 consistently altered DNA regions, containing 11 enzymes in the glycolysis pathway in addition to known cancer‐driving genes. Furthermore, exogenous expression of hexokinase and enolase enzymes in an experimental immortalization system altered the subsequent copy number status of the corresponding endogenous loci, supporting the hypothesis that these metabolic genes act as drivers within the conserved CNA amplification regions. Taken together, these results demonstrate that metabolic stress acts as a selective pressure underlying the recurrent CNAs observed in human tumors, and further cast genomic instability as an enabling event in tumorigenesis and metabolic evolution. Synopsis A pan‐cancer and cross‐species analysis of recurrent copy number alteration (CNA) patterns reveals that coordinated CNA of energy metabolism genes provides a selective advantage during tumorigenesis by promoting glycolytic metabolism. Amplifications of glycolysis‐associated genes are conserved and enriched in tumors with high genomic instability, with glycolysis thus functioning as an “oncopathway” in regard to shaping the cancer CNA genome. Copy number signatures predict the glycolytic activity of primary breast cancers and breast cancer cell lines. Genetic manipulation of glycolysis genes prior to the initiation of genomic instability alters the resulting genomic copy number landscape at the endogenous loci. Complex but coordinated DNA copy number changes can contribute to cancer phenotypes in genomically unstable tumors. Graphical Abstract A pan‐cancer and cross‐species analysis of recurrent copy number alteration (CNA) patterns reveals that coordinated CNA of energy metabolism genes provides a selective advantage during tumorigenesis by promoting glycolytic metabolism.

Ampk is an energy gatekeeper that responds to decreases in ATP by inhibiting energy-consuming anabolic processes and promoting energy-generating catabolic processes. Recently, we showed that Lkb1, an understudied kinase in B lymphocytes and a major upstream kinase for Ampk, had critical and unexpected roles in activating naïve B cells and in germinal center formation. Therefore, we examined whether Lkb1 activities during B cell activation depend on Ampk and report surprising Ampk activation with in vitro B cell stimulation in the absence of energy stress, coupled to rapid biomass accumulation. Despite Ampk activation and a controlling role for Lkb1 in B cell activation, Ampk knockout did not significantly affect B cell activation, differentiation, nutrient dynamics, gene expression, or humoral immune responses. Instead, Ampk loss specifically repressed the transcriptional expression of IgD and its regulator, Zfp318 . Results also reveal that early activation of Ampk by phenformin treatment impairs germinal center formation but does not significantly alter antibody responses. Combined, the data show an unexpectedly specific role for Ampk in the regulation of IgD expression during B cell activation.

Expansion of antigen-experienced CD8 + T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer 1 . Interleukin-2 (IL-2) acts as a key regulator of CD8 + cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability 2 , 3 . Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE 2 ), a known negative regulator of immune response in the tumour microenvironment 4 , 5 , is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8 + TILs via the PGE 2 receptors EP2 and EP4. Mechanistically, PGE 2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγ c chain, resulting in defective assembly of IL-2Rβ–IL2Rγ c membrane dimers. This results in impaired IL-2–mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE 2  signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE 2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential. Prostaglandin E2 from the tumour microenvironment impairs interleukin-2 sensing by tumour-infiltrating lymphocytes, restricting proliferative response and promoting T cell death via metabolic impairment and ferroptosis. 

Expansion of antigen-experienced CD8 T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer . Interleukin-2 (IL-2) acts as a key regulator of CD8 cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability . Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE ), a known negative regulator of immune response in the tumour microenvironment , is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8 TILs via the PGE receptors EP2 and EP4. Mechanistically, PGE inhibits IL-2 sensing in TILs by downregulating the IL-2Rγ chain, resulting in defective assembly of IL-2Rβ-IL2Rγ membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE  signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.

Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions. These patterns are indicative of conserved selection pressures, but cannot be fully explained by known oncogenes and tumor suppressor genes. Using integrative analysis of CNA data from patient tumors and experimental systems, we report that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including FDG-avidity of patient tumors, and increased proliferation. The primary glycolysis-linked CNA signature is associated with p53 mutation and shows coordinate amplification of glycolytic genes and other cancer-linked metabolic enzymes including TIGAR and RPIA. In contrast, alternative signatures involve both different mechanisms of tumor suppression loss (eg, MDM2 amplification) and different glycolysis enzyme isoforms. Furthermore, a cross-species CNA comparison identified 21 conserved CNA regions, containing 13 enzymes in the glycolysis and pentose phosphate pathways in addition to known cancer driving genes. In validation experiments, exogenous expression of hexokinase and enolase enzymes resulted in reduced propensities for amplifications at the corresponding endogenous loci. Our findings support metabolic stress as a selective pressure underlying the recurrent CNAs observed in human tumors, and further cast genomic instability as an enabling event in tumorigenesis and metabolic evolution.

Anti-PD1 therapies are primarily thought to rely on functional T cell responses; yet tumors with limited T cell infiltration can still benefit, suggesting alternative mechanisms contribute to therapeutic efficacy. Indeed, we found that myeloid-rich, T cell-poor tumor models respond to anti-Pd1, and this is dependent on a cancer cell-macrophage crosstalk mediated by cancer cell expression. Mechanistically, we found that cancer cells with decreased expression (C ), which occurs in ∼50% of all human cancers, reorganize zinc compartmentalization by upregulating the zinc importer Slc39a9 at the plasma membrane. Increased cancer cell plasma membrane Slc39a9 leads to intracellular zinc accumulation in cancer cells and depletion of zinc in the tumor microenvironment (TME), resulting in zinc-starved tumor-associated macrophages (TAMs) with reduced phagocytic activity. Restoring zinc availability in TAMs-via dietary supplementation or Slc39a9 knockdown in cancer cells-reprograms TAMs to a pro-phagocytic state and sensitizes tumors to anti-Pd1 therapy. Remarkably, Slc39a9 knockdown tumors respond to anti-Pd1 in Rag1 mice, and co-injection of zinc-replete macrophages is sufficient to drive an anti-Pd1 response in immunodeficient mice, demonstrating the T cell-independent nature of this response. Clinically, TAMs from cancer patients show reduced zinc and phagocytosis gene signatures. Moreover, patients with lower circulating zinc levels have significantly worse time-to-event outcomes than those with higher levels. Together, these findings uncover a previously unrecognized mechanism by which cancer cells outcompete TAMs for zinc, impairing their function and limiting anti-Pd1 efficacy. They also provide evidence that macrophages alone, without T cells, can enhance anti-PD1 response through zinc-mediated reprogramming of phagocytosis.

Approximately 50% of cancers exhibit decreased CDKN2A expression ( CDKN2A Low ), which is linked to immune checkpoint blockade (ICB) resistance. While CDKN2A is traditionally recognized as a tumor suppressor and cell cycle regulator, we have previously put forth a new paradigm demonstrating its role in intracellular metabolic reprogramming. Whether the metabolic derangement due to CDKN2A loss alters metabolites within the tumor microenvironment (TME) and how that affects the immune compartment and ICB response has never been investigated. Here we found that CDKN2A Low cancer cells reorganize zinc compartmentalization by upregulating the zinc importer SLC39A9 in the plasma membrane, leading to intracellular zinc accumulation in cancer cells and concurrent zinc depletion in the TME. This competition for zinc results in zinc-starved tumor-associated macrophages (TAMs), leading to reduced phagocytic activity. Increasing zinc in TAMs through multiple approaches, including a dietary intervention that increases availability of TME zinc, re-educates these TAMs to a pro-phagocytic phenotype. Remarkably, both knockdown of Slc39a9 in cancer cells or providing a high zinc diet sensitizes Cdkn2a Low tumors to ICB. TAMs, not T cells, are indispensable for ICB response. Clinically, TAMs from CDKN2A Low cancer patients have decreased zinc signatures, corresponding to reduced phagocytosis signatures. Moreover, patients with low circulating zinc levels have reduced time-to-event outcomes compared to those with higher zinc levels. Our work reveals a previously unrecognized mechanism through which CDKN2A Low cancer cells outcompete TAMs for zinc, directly disrupting their function and ICB efficacy.Approximately 50% of cancers exhibit decreased CDKN2A expression ( CDKN2A Low ), which is linked to immune checkpoint blockade (ICB) resistance. While CDKN2A is traditionally recognized as a tumor suppressor and cell cycle regulator, we have previously put forth a new paradigm demonstrating its role in intracellular metabolic reprogramming. Whether the metabolic derangement due to CDKN2A loss alters metabolites within the tumor microenvironment (TME) and how that affects the immune compartment and ICB response has never been investigated. Here we found that CDKN2A Low cancer cells reorganize zinc compartmentalization by upregulating the zinc importer SLC39A9 in the plasma membrane, leading to intracellular zinc accumulation in cancer cells and concurrent zinc depletion in the TME. This competition for zinc results in zinc-starved tumor-associated macrophages (TAMs), leading to reduced phagocytic activity. Increasing zinc in TAMs through multiple approaches, including a dietary intervention that increases availability of TME zinc, re-educates these TAMs to a pro-phagocytic phenotype. Remarkably, both knockdown of Slc39a9 in cancer cells or providing a high zinc diet sensitizes Cdkn2a Low tumors to ICB. TAMs, not T cells, are indispensable for ICB response. Clinically, TAMs from CDKN2A Low cancer patients have decreased zinc signatures, corresponding to reduced phagocytosis signatures. Moreover, patients with low circulating zinc levels have reduced time-to-event outcomes compared to those with higher zinc levels. Our work reveals a previously unrecognized mechanism through which CDKN2A Low cancer cells outcompete TAMs for zinc, directly disrupting their function and ICB efficacy.

Approximately 50% of cancers exhibit decreased CDKN2A expression (CDKN2ALow), which is linked to immune checkpoint blockade (ICB) resistance. While CDKN2A is traditionally recognized as a tumor suppressor and cell cycle regulator, we have previously put forth a new paradigm demonstrating its role in intracellular metabolic reprogramming. Whether the metabolic derangement due to CDKN2A loss alters metabolites within the tumor microenvironment (TME) and how that affects the immune compartment and ICB response has never been investigated. Here we found that CDKN2ALow cancer cells reorganize zinc compartmentalization by upregulating the zinc importer SLC39A9 in the plasma membrane, leading to intracellular zinc accumulation in cancer cells and concurrent zinc depletion in the TME. This competition for zinc results in zinc-starved macrophages, leading to reduced phagocytic activity. Remarkably, restoring zinc levels in the TME through a dietary intervention re-educates macrophages to a pro-phagocytic phenotype, sensitizing CDKN2ALow tumors to ICB. Unexpectedly, T cells are not required for this response. Clinically, macrophages from CDKN2ALow cancer patients have decreased zinc signatures, corresponding to reduced phagocytosis signatures. Moreover, patients with low circulating zinc levels have reduced time-to-event outcomes compared to those with higher zinc levels. Our work reveals a previously unrecognized mechanism through which CDKN2ALow cancer cells outcompete macro-phages for zinc, directly disrupting their function and ICB efficacy.Competing Interest StatementThe authors have declared no competing interest.

Immunotherapy has produced disappointing results in recurrent ovarian cancer (OC). However, the prognostic value of tumour-infiltrating lymphocytes (TILs) is largely based on the analysis of treatment-naive tumours. To understand the immunobiology of recurrent cancers, and their evolution, we profiled 170 patient-matched primary-recurrent OC samples from 69 patients of two independent cohorts. By capturing heterogeneous TIL distributions, we identified four immune phenotypes associated with differential prognosis, TILs states and TILs:myeloid networks, which dictate malignant evolution after chemotherapy and recurrence. Notably, recurrent tumours recapitulate the immunogenic patterns of original cancers. Mirroring inflamed human OC, preclinical recurrent Brca1mut tumours maintained activated TILs:dendritic cells (DCs) niches and immunostimulatory tumour-associated macrophages (TAMs). Conversely, recurrent Brca1wt tumours displayed loss of TILs:DCs niches and accumulated immunosuppressive myeloid networks featuring Trem2/ApoEhigh TAMs and Nduf4l2high/Galectin3high malignant states. Our study highlights that persistent immunogenicity in recurrent OC is governed by the crosstalk between dissimilar myeloid cells and TILs, which is BRCA-dependent.