Extended Data Table 1. Tumor-enriched shRNAs from secondary screen.

Secondary screens were performed with a total of ~15 shRNAs for each gene of interest. a, Results from secondary screen of T cell dysfunction pool shRNA library. Genes for which at least 3 shRNAs showed ≥4 fold enrichment in tumors are listed, along with a brief description of their function. b, Results from secondary screen of kinase and phosphatase shRNA libraries.

a
	Symbol	Total # shRNAs	Enrichment (fold)	Function
1	Dgkz	6	5.2 – 14.0	Phosphorylates and thereby inactivates DAG
2	Egr2	6	4.0 – 10.2	Transcription factor involved in T cell unresponsiveness, expression of Cblb
3	Smad2	5	6.7 – 30.3	TGF beta signaling pathway
4	Cblb	5	4.1 – 10.8	E3 ubiquitin ligase (degradation of TCR and signaling molecules; ko mice reject tumors
5	Inpp5b	5	4.3 – 9.5	Inositol polyphosphate-5-phosphatase, hydrolyzes PIP2
6	Socs1	5	4.1 – 8.5	Inhibitor of cytokine signaling
7	Jun	5	5.2 – 6.4	Persistent AP-1 activation in turn or-infiltrating T cells leads to upregulated PD-1
8	Vamp7	4	4.0 – 11.3	Vesicle associated transmembrane protein
9	Dgka	4	5.0 – 10.2	Phosphorylates and thereby inactivates DAG
10	Mdfic	4	4.4 – 10.0	Inhibits viral gene expression, interacts with cyclin T1 and T2
11	Nptxr	4	4.0 – 7.2	Pentraxin Receptor
12	Socs3	4	4.6 – 6.3	Inhibitor of cytokine signaling
13	Entpd1	3	6.5 – 13.3	Extracellular degradation of ATP to AMP {an inhibitory signal through AMP kinase)
14	Pdz1lp1	3	4.8 – 12.9	Pdzk1 interacting protein, expression correlates with tumor progression
15	F11r	3	4.6 – 6.8	Cell Migration
16	Fyn	3	4.1 – 6.5	Inhibits activation of resting T cells (through Csk)
17	Ypel2	3	4.6 – 5.1	Function unknown

b
	Symbol	Total # shRNAs	Enrichment (fold)	Function
1	Rbks	6	4.0 – 12.8	Ribokinase, carbohydrate metabolism
2	Pkd1	6	4.9 – 9.9	Cell cycle arrest (activates JAK/STAT pathway)
3	Ppp2r2d	5	4.0 – 17.2	Regulatory subunit of PP2A phosphatase
4	Eif2ak3	5	4.8 – 13.4	ER stress sensor, resistance of cancer cells to chemotherapy
5	Ptpn2	5	4.7 – 7.4	Inhibitor of T cell and cytokine signaling
6	Hipk1	4	4.5 – 12.3	Interacts with p53 and c-myb, knockout mice develop fewer carcinogen-induced tumors
7	Grk6	4	4.2 – 11	Regulator of particular G-protein coupled receptors
8	Cdkn2a	4	4.1 – 7.2	G1 cell cycle arrest and apoptosis in T cells
9	Sbf1	4	4.8 – 6.9	Activates MTMR2, which dephosphorylates PI(3)P and PI(3,5)P2
10	Ipmk	4	4.0 – 6.9	Inositol polyphosphate kinase, nuclear functions such as chromatin remodeling
11	Rock1	4	4.1 – 6.5	Rho kinase, inhibitors have shown activity in mouse models of cancer
12	Stk17b	4	4.0 – 6.4	Inhibitor of T cell signaling forms complex with protein kinase D
13	Mast2	4	4.1 – 5.1	Microtubule-associated serine/threonine kinase
14	Arhgap5	3	6.0 – 15.7	Negative regulator of Rho GTPases, inhibition can reduce cancer cell invasion
15	Alk	3	9.6 – 13.5	Anaplastic lymphoma kinase (translocation of nucleophosmin and ALK in ALCL)
16	Nuak	3	4.5 – 13.1	Member of AMP-activated protein kinase-related kinase family, oncogene in melanoms
17	Akap8l	3	4.4 – 11.8	A-kinase anchoring protein, recruits cAMP-dependent protein kinase (PKA) to chromatin
18	Pdp1	3	4.1 – 9.8	Pyruvate dehydrogenase phosphatase 1, regulation of glucose metabolism
19	Yes1	3	5.4 – 9.7	Src family kinase, oncogene in several tumors
20	Met	3	4.1 – 8.9	Receptor tyrosine kinase, involved in hepatocellular and other cancers
21	Ppm1g	3	6.2 – 8.2	Dephosphorylates spliceosome substrates and histones H2A-H2B
22	Blvrb	3	5.3 – 8.0	Biliverdin reductase, also transcription factor, arrest of cell cycle
23	Tnk1	3	5.2 – 7.6	Downregulates Ras pathway (phosphorylation of Grb2), inhibition of NF-kB pathway
24	Prkab2	3	4.1 – 7.0	Subunit of AMP kinase, inhibits fatty acid synthesis and mTOR pathway
25	Trpm7	3	4.9 – 5.9	Ion channel and serine-threonine kinase
26	Ppp3cc	3	4.2 – 4.4	Regulatory subunit of calcineurin (phosphatase in T cell receptor signaling)