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Lung cancer recruits tumor-associated macrophages (TAMs) massively, whose predominantly pro-tumor M2 phenotype leads to immunosuppression. Dihydroartemisinin (DHA) has been proven to remodel TAM into an anti-tumor M1 phenotype at certain concentrations in the present study, which was hypothesized to facilitate anti-lung cancer immunotherapy. However, how DHA remodels the TAM phenotype has not yet been uncovered. Our previous work revealed that DHA could trigger ferroptosis in lung cancer cells, which may also be observed in TAM thereupon. Sequentially, in the current study, DHA was found to remodel TAM into the M1 phenotype in vitro and in vivo. Simultaneously, DHA was observed to trigger ferroptosis in TAM and cause the DNA damage response and NF-κB activation. Conversely, the DHA-induced DNA damage response and NF-κB activation in TAM were attenuated after the inhibition of ferroptosis in TAM using an inhibitor of ferroptosis. Importantly, a ferroptosis inhibitor could also abolish the DHA-induced phenotypic remodeling of TAM toward the M1 phenotype. In a nutshell, this work demonstrates that DHA-triggered ferroptosis of TAM results in DNA damage, which could activate downstream NF-κB to remodel TAM into an M1 phenotype, providing a novel strategy for anti-lung cancer immunotherapy. This study offers a novel strategy and theoretical basis for the use of traditional Chinese medicine monomers to regulate the anti-tumor immune response, as well as a new therapeutic target for TAM phenotype remodeling.

Xylaria wuzhishanensis Y.P. Wu & Q.R. Li, sp. nov. (Fig. 5) MycoBank number: MB 842170 Type:— CHINA, Hainan Province, Wuzhishan City, Wuzhishan Nature Reserve (18.541805°N, 109.412245°E), elev. 892 m, on dead wood of a plant roots (Oleaceae sp.), November 2020, Youpeng Wu and Lili Liu, 2020WZS35 (GMB0074, holotype; KUN-HKAS 12634, isotype; ex-type living culture, GMBC0074). Etymology: Referring to its collection location, Wuzhishan Mountain from where the species was first isolated (China). Saprobic on dead wood roots, forming on the host surface. Sexual morph: Stromata 0.3–0.8 cm long × 0.6–1.2 cm broad (x = 0.6 × 0.8 cm, n = 10), semiglobular or irregularly globose, whole stromata up to with flattened or slightly convex top. Surface of stromata black, with raised blackish dots. Perithecia 300–600 μm high × 200–400 μm diam. (x = 400 × 300 μm, n = 10), oval to spherical, embedded, closely arranged, interior white. Ostioles papillate, surrounded with white tissue. Asci 235–366 × 11–20 μm (x = 293 × 14.2 μm, n = 30), 8-spored, unitunicate, cylindrical, long-stipitate, apically rounded, with a J+, rectangular or urn-shaped, apical ring, blue staining in Melzer’s reagent, 6.7–10.5 μm (x = 8.7 μm, n = 30) high, 4.2–6.5 μm (x = 5.3 μm, n = 30) wide. Ascospores 23–30.5 × 7–9 μm (x = 26.5 × 8 μm, n=30), brown to black, unicellular, ellipsoid to inequilateral, with broadly rounded ends, smooth, with a conspicuous slanted germ slit nearly one-third spore-length, lacking appendages and sheaths. Asexual morph: Undetermined. Culture characteristics: Colonies on OA reaching 3–4 mm diam. after 2 weeks at 25 °C. White at first, white at first, upright, velvety with irregular outgrowths or furrows, with a peripheral fan-shaped extension spreading toward the edge; reverse light grey in the center, white marginal area. After 4 weeks, colonies on OA reaching 9 cm diam., white greyish, velvety or inflorescence, appressed with entire margins; reverse black, with brownish ring. No conidia were observed. Notes: Based on the multi-gene phylogenetic analyses (Fig. 1), X. wuzhishanensis is most closely related to X. schweinitzii. Morphologically, X. wuzhishanensis differs from X. schweinitzii by its semi-globular or irregularly globose stromata. Xylaria wuzhishanensis shows similar traits of X. atrosphaerica (Cooke & Massee) Callan & J.D. Rogers, X. globosa (Spreng. ex Fr.: Fr.) Mont., and X. lepidota Y.M. Ju et al. with semiglobular or irregularly globose stromata. But, X. wuzhishanensis can distinguish from X. atrosphaerica by its larger ascospores (23–30.5 × 7–9 μm vs. 17–25 × 6–10 μm) with a shorter germ slit (Callan et al. 1990). The surface of stroma lacks crackle of X. wuzhishanensis, which can make a distinction between X. globosa and X. lepidota (Ju et al. 2009, Fournier et al. 2018)., Published as part of Wu, You-Peng, Pi, Yin-Hui, Long, Si-Han, Liu, Li-Li, Zhang, Xu, Long, Qing-De, Lin, Yan, Kang, Ying-Qian, Kang, Ji-Chuan, Wijayawardene, Nalin N. & Li, Qi-Rui, 2022, Morphology and phylogeny reveal two novel Xylaria (Xylariaceae) species from China, pp. 130-146 in Phytotaxa 550 (2) on page 141, DOI: 10.11646/phytotaxa.550.2.3, http://zenodo.org/record/6641065, {"references":["Callan, B. E. & Rogers, J. D. (1990) Teleomorph-anamorph connections and correlations in some Xylaria species. Mycotaxon 36: 343 - 369.","Ju, Y. M., Hsieh, H. M., Vasilyeva, L. & Akulov, A. (2009) Three new Xylaria species from Russian Far East. Mycologia 101: 548 - 553. http: // doi. org / 10.3852 / 08 - 188","Fournier, J., Lechat, C. & Courtecuisse, R. (2018) The genus Xylaria sensu lato (Xylariaceae) in Guadeloupe and Martinique (French West Indies) I. Taxa with penzigioid stromata. Ascomycete. org 10 (4): 131 - 176. http: // doi. org / 10.25664 / ART- 0239"]}

Xylaria sylvatica Y.P. Wu & Q.R. Li, sp. nov. (Fig. 4) MycoBank number: MB 842171 Type:— CHINA. Guizhou Province: Guiyang City, Guiyang Forest Park (26.2329°N, 106.451958°E), elev. 1142 m, on dead wood of unidentified plant, June 2021, Youpeng Wu, 2021GYSLGY6 (GMB0076, holotype; KUN-HKAS 122632, isotype; ex-type living culture, GMBC0076). Etymology: Refers to a forest habitat for specimen collection. Saprobic on dead wood, forming on the host surface. Sexual morph: Stromata 0.6–1.7 cm long × 0.2–0.5 cm broad (x = 1.2 × 0.4 cm, n = 10), upright, usually solitary, unbranched, cylindrical or clavate, fertile inflated at apex, texture soft, internally white. Surface of stromata gray to black, conspicuous cracked. Stalk well defined and easy to distinguish. Perithecia 500–700 μm high × 300–700 μm broad (x = 600 × 400 μm, n = 10), oval, sphaerical to subsphaerical, embedded, closely arranged, tissue between the perithecia is white. Ostioles inconspicuous. Asci 224–313 × 10.5–20.5 μm (x = 260 × 15 μm, n = 30), 8-spored, unitunicate, cylindrical, long-stipitate, apically rounded, with a J+, wedge-shaped apical ring, blue staining in Melzer’s reagent, 9–15 μm (x = 12.2 μm, n = 30) high, 4–7 μm (mean = 5.3 μm, n = 30) wide. Ascospores 23–28.5 × 7–9.5 μm (x = 25 × 8 μm, n = 30), green grey, unicellular, ellipsoid to inequilateral, with broadly rounded ends, smooth, with a sigmoid germ slit nearly half spore-length, lacking appendages and sheaths. Asexual morph: Undetermined. Culture characteristics: Colonies on OA reaching 3–4 mm diam. after 2 weeks at 25 °C. White at first, with regular margins, upright, velvety, with irregular outgrowths or furrows, with a peripheral fan-shaped extension spreading toward the edge; reverse blackish-brown in the center, white marginal area. After 4 weeks, Colonies on OA reaching 9 cm diam., white greyish, velvety or inflorescence, appressed with entire margins; reverse black, with brownish ring. No conidia were observed. Notes: Phylogenetic analyses (Fig. 1) indicated that X. sylvatica was closely related to X. spinulosa and X. haemorrhoidalis but formed a distinct lineage. However, X. sylvatica is distinguish from X. spinulosa by its lacking long thorns on the stromatal surface, and larger ascospores (23–28.5 × 7–9.5 μm vs. 19–23 × 6.5–8.5 μm) with a sigmoid germ slit. Xylaria sylvatica differs from X. haemorrhoidalis by its upright, solitary, unbranched, cylindrical or clavate stromata (Li et al. 2017). Morphologically, Xylaria sylvatica shows similar traits of X. martinicensis J. Fourn. & Lechat., and X. squamulosa F. San Martín & J.D. Rogers., with upright, long stipitate, cylindrical or clavate stromata with fertile inflated at apex, conspicuous cracked or wrinkled on the surface of stromata. But, X. martinicensis have smaller ascospores (13–16.5 × 6–7.5 μm vs. 23–28.5 × 7–9.5 μm), with a narrow but conspicuous, straight, longitudinally oriented germ slit, which can make a distinction for X. sylvatica (Fournier et al. 2020). Xylaria squamulosa differs from X. sylvatica by larger ascospores (29–40 × 11–14 μm vs. 23–28.5 × 7–9.5 μm) with a straight germ slit nearly spore-length (San Martín et al. 1989)., Published as part of Wu, You-Peng, Pi, Yin-Hui, Long, Si-Han, Liu, Li-Li, Zhang, Xu, Long, Qing-De, Lin, Yan, Kang, Ying-Qian, Kang, Ji-Chuan, Wijayawardene, Nalin N. & Li, Qi-Rui, 2022, Morphology and phylogeny reveal two novel Xylaria (Xylariaceae) species from China, pp. 130-146 in Phytotaxa 550 (2) on pages 137-141, DOI: 10.11646/phytotaxa.550.2.3, http://zenodo.org/record/6641065, {"references":["Li, Q. R., Liu, L. L., Zhang, X., Shen, X. C. & Kang, J. C. (2017) Xylaria spinulosa sp. nov. and X. atrosphaerica from southern China. Mycosphere 8 (8): 1070 - 1079. http: // doi. org / 10.5943 / mycosphere / 8 / 8 / 8","Fournier, J., Lechat, C. & Courtecuisse, R. (2020) The genus Xylaria sensu lato (Xylariaceae) in Guadeloupe and Martinique (French West Indies) III. Taxa with slender upright stromata. Ascomycete. org 12 (3): 81 - 164. http: // doi. org / 10.25664 / ART- 0302","San Martin, G. F. & Rogers, J. D. (1989) A preliminary account of Xylaria of Mexico. Mycotaxon 34 (2): 368."]}

Xylaria atrosphaerica (Cooke & Massee) Callan & J.D. Rogers, Mycotaxon 36 (2): 349 (1990) (Fig. 2) Synonymy: Hypoxylon atrosphaericum Cooke & Massee, Grevillea 22(no. 103): 68 (1894) Penzigia atrosphaerica (Cooke & Massee) J.N. Mill., Monograph Univ. Puerto Rico, Series B 2: 212 (1934) Kretzschmaria atrosphaerica (Cooke & Massee) P.M.D. Martin, Jl S. Afr. Bot. 36(2): 79 (1970) Kretzschmaria atrosphaerica (Cooke & Massee) P.M.D. Martin, Jl S. Afr. Bot. 42(1): 74 (1976) MycoBank number: MB 127393 Saprobic on dead wood, forming on the host surface. Sexual morph: Stromata semiglobular or irregularly globose, pulvinate, 0.4‒1.8 mm high × 1.4‒3.2 mm broad (x = 1.4 × 2.3 mm, n = 10), with flattened or slightly convex top. Exterior grey dark to black, roughened by fine cracks and ostioles; interior whithish to light grey. Perithecia 0.3‒0.8 mm diam., completely immersed, sphaerical. Ostioles inconspicuous. Asci 182‒288 × 12.3‒20 μm (x = 237 × 16.1 μm, n = 30), unitunicate, 8-spored, cylindrical, long-stipitate, apically rounded, with a J +, wedge-shaped apical ring, blue staining in Melzer’s reagent, 7–12 μm (x = 10 μm, n = 30) high, 3.5–7 μm (x = 5.4 μm, n = 30) wide. Ascospores 20.5–25.5 × 6.5–10 μm (x = 22.7 × 7.8 μm, n = 30), brownish-black, unicellular, ellipsoid to inequilateral, with broadly rounded ends, smooth, with a sigmoid germ slit nearly half spore-length, lacking appendages and sheaths. Asexual morph: Undetermined. Specimens examined: CHINA, Guizhou Province, Duyun City, Doupengshan Nature Reserve (26.223062°N, 107.22846°E), elev. 1086 m, on dead wood of unidentified plant, June 2021, Youpeng Wu, 2021DPS13 (GMB0077, KUN-HKAS 122633; living culture, GMBC 0077). Culture characteristics: Colonies on OA reaching 4–5 mm diam. after 2 weeks at 25 ° C. White at first, with regular margins, becoming moderately radiating furrows spreading toward the edge, medium becoming black from central; reverse greyish black ring in the center, white marginal area. After 4 weeks, colonies on OA reaching 9 cm diam., white, velvety, appressed with entire margins; reverse dark black. No conidia were observed. Notes: Hypoxylon atrosphaericum Cooke & Massee collected from Queensland was described originally by Cooke (1894). Rogers et al. (1987) described the asexual morph of Penzigia atrosphaerica collected from Indonesia. However, based primarily on the nature of cultures, Callan & Rogers (1990) placed them in the genus Xylaria. Morphologically, our new collection (GMB0077) is congruent with X. atrosphaerica having semi-globular or irregularly globose stromata, grey dark to black, internally white; surface roughened by fine cracks and ostioles and perithecial mounds inconspicuous, brownish-black, ellipsoid-inequilateral, smooth ascospores (17–25 × 6–10 μm), with oblique to spiral germ slit, nearly 1/2 spore-length, lacking sheaths and appendages. Phylogenetic analyses showed that GMB0077 resembles with X. atrosphaerica (HAST 91111214) with high statistical support (100% ML, 1.00 BYPP; Fig. 1)., Published as part of Wu, You-Peng, Pi, Yin-Hui, Long, Si-Han, Liu, Li-Li, Zhang, Xu, Long, Qing-De, Lin, Yan, Kang, Ying-Qian, Kang, Ji-Chuan, Wijayawardene, Nalin N. & Li, Qi-Rui, 2022, Morphology and phylogeny reveal two novel Xylaria (Xylariaceae) species from China, pp. 130-146 in Phytotaxa 550 (2) on page 134, DOI: 10.11646/phytotaxa.550.2.3, http://zenodo.org/record/6641065, {"references":["Rogers, J. D., Callan, B. E. & Samuels, G. J. (1987) The Xylariaceae of the rain forests of north Sulawesi (Indonesia). Mycotaxon 29: 113 - 172. https: // doi. org / 10.1007 / BF 00436682","Callan, B. E. & Rogers, J. D. (1990) Teleomorph-anamorph connections and correlations in some Xylaria species. Mycotaxon 36: 343 - 369."]}

Xylaria cubensis (Mont.) Fr., Nova Acta Regia Soc. Sci. Upsal. (Ser. 3) 1: 126. 1851; sensu Rogers (1984) (Fig. 3) Synonymy: Hypoxylon cubense Mont., Annls Sci. Nat., Bot., sér. 2 13: 345 (1840) MycoBank number: MB 179243 Saprobic on dead tree trunk, forming on the host surface. Sexual morph: Stromata solitary, cylindric-clavate, usually unbranched, 2.2–5.8 cm long × 0.6–1.2. cm broad (x = 3.6 × 0.8 cm, n = 10), with short or long stipe from a pannose base, externally copper brown to brownish-black, internally white. Surface smooth to slightly rough with fine cracks. Perithecia ovoid, 0.4–0.8 mm diam., ostioles inconspicuous to conspicuous, prominent. Ostioles papillae. Asci 107– 162 × 5.3‒8.2 μm (x = 124 × 6.8 μm, n = 30), unitunicate, 8-spored, cylindrical, long-stipitate, apically rounded, with a J +, rectangular, apical ring, blue staining in Melzer’s reagent, 1.5–2.5 μm (x = 2.2 μm, n = 30) high, 1.5–2 μm (x = 1.8 μm, n = 30) wide. Ascospores 8–9.5 × 4–5 μm (x = 8.5 × 4.5 μm, n = 30), brown to dark brown, unicellular, ellipsoid-inequilateral, with widely rounded ends, smooth, with a straight central germ slit along much less than sporelength, lacking appendages and sheaths. Asexual morph: Undetermined. Specimens examined: CHINA, Hainan Province, Haikou City, Huoshankou Geological Park (19.554365°N, 110.13203°E), elev. 152 m, on dead wood of unknown plant roots, November 2020, Youpeng Wu and Lili Liu, 2020HSK4 (GMB0075, KUN-HKAS 122631; living culture GMBC 0075). Culture characteristics: Colonies on OA reaching 4–5 mm diam. after 2 weeks at 25 ° C. White at first, with regular margins, then with a peripheral ring-shaped extension spreading toward the edge of the Petri dish; reverse milky white in the center, light white marginal area. After 4 weeks, colonies on OA reaching 9 cm, stromata arising from concentric zones, cylindrical, tapering upwards, flexuous, unbranched; reverse light grey, emerge black dots. No conidia were observed. Notes: Xylaria cubensis is a common species and was reported from Africa, North and South America, Asia, Oceania and China (Ma et al. 2012). Xylaria cubensis is mainly characterized by its smooth surface with papillate ostioles, copper-colored, brown or brownish-black clavate stromata with rounded fertile apices and small ascospores mostly with unclear germ slit (Rogers 1984), which has been reported from Taiwan (Ju et al. 1999) and Guizhou, Jilin, Yunnan provinces in China (Ma et al. 2012). Our specimens examined in this study display the same characters of X. cubensis described by Rogers (1984) and Ma et al. (2012), such as long stipe from a pannose base, with papillate ostioles of stromata surface, externally copper brown to brownish-black, internally white; ascospores with unclear germ slit less than spore-length, lacking appendages and sheaths. Phylogenetic analyses of a combined alignment of β-tubulin, rpb 2 and α-actin genes showed that the strain GMB0075 grouped with X. cubensis (HAST 515) with high statistical support (100% ML, 1.00 BYPP; Fig. 1). This is the first record of X. cubensis from Hainan province, China., Published as part of Wu, You-Peng, Pi, Yin-Hui, Long, Si-Han, Liu, Li-Li, Zhang, Xu, Long, Qing-De, Lin, Yan, Kang, Ying-Qian, Kang, Ji-Chuan, Wijayawardene, Nalin N. & Li, Qi-Rui, 2022, Morphology and phylogeny reveal two novel Xylaria (Xylariaceae) species from China, pp. 130-146 in Phytotaxa 550 (2) on page 137, DOI: 10.11646/phytotaxa.550.2.3, http://zenodo.org/record/6641065, {"references":["Rogers, J. D. (1984) Xylaria cubensis and its anamorph Xylocoremium flabelliforme, Xylaria allantoidea, and Xylaria poitei in continental United States. Mycologia 76: 912 - 923. https: // doi. org / 10.1080 / 00275514.1984.12023929","Ju, Y. M. & Rogers, J. D. (1999) The Xylariaceae of Taiwan (excluding Anthostomella). Mycotaxon 73: 343 - 440."]}